Interleukin-17 and innate immunity in infections and chronic inflammation.

Journal of Autoimmunity xxx (2015) 1e11

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Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm

Review

Interleukin-17 and innate immunity in infections and chronic inflammation Natasa Isailovic a, Kenji Daigo b, Alberto Mantovani b, c, **, 1, Carlo Selmi a, d, *, 1 a

Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy c Humanitas University, Rozzano, Italy d BIOMETRA Department, University of Milan, Milan, Italy b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 April 2015 Accepted 26 April 2015 Available online xxx

Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Psoriasis Psoriatic arthritis Infection Secukinumab Ixekizumab Brodalumab

1. Introduction Innate immunity represents the first and phylogenetically oldest line of defense against infections for all multicellular organism including plants and insects. In general terms, innate immunity provides the initial acute inflammatory response to microorganisms to prevent, control and eliminate infections while it has the ability to modulate and stimulate adaptive immune responses usually secreting different kind of cytokines to activate and attract cells that are considered effector cells of adaptive immunity [1]. The acute inflammatory response is generally selflimiting and results in tissue repair and return of tissue homeostasis while the persistence of inflammatory stimuli or the dysregulation of resolution mechanisms result in chronic

* Corresponding author. Division of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy. ** Corresponding author. Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy. E-mail addresses: [email protected] (A. Mantovani), [email protected] (C. Selmi). 1 AM and CS contributed equally to this manuscript.

inflammation, recognized to be a key underlying factor in the progression of complex diseases, including metabolic and cardiovascular ones [2]. CD4þ T cells are the central players in the adaptive immune response [3] and naïve CD4þ T cells upon stimulation and activation differentiate into distinct subsets according to the corresponding cytokine profile. Two separate Th subsets were originally defined by the secretion of interferon g (IFNg, for Th1) or interleukin 4 (IL-4, for Th2) [4]. Th1 are helper cells involved in the elimination of intracellular pathogens and characterize organspecific autoimmune diseases. The key Th1 effector-cytokines include IFNg, lymphotoxin a (Lfa), and IL-2 [5,6]. Th2 helper cells play major role in immune responses against extracellular parasites, in the pathogenesis of asthma and other related allergic conditions. Th2 cells are significant producers of IL-4, IL-5, IL-9, IL-13, IL-10, IL-25, and amphiregulin [7]. Over the past years, additional effector populations of CD4þ T cell were identified and consequently referred to as Th9 [8], Th17, and Th22 [9,10] with a considerable degree of plasticity [11] and Th17 characterized by the production of IL-17 as the signature cytokine [12]. The IL-17 cytokine family includes six members, i.e. IL-17A, IL-17B, IL-17C, IL-17D, IL-17E - referred also as IL-25 and IL-17F (Table 1). IL-17A

http://dx.doi.org/10.1016/j.jaut.2015.04.006 0896-8411/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: N. Isailovic, et al., Interleukin-17 and innate immunity in infections and chronic inflammation, Journal of Autoimmunity (2015), http://dx.doi.org/10.1016/j.jaut.2015.04.006

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N. Isailovic et al. / Journal of Autoimmunity xxx (2015) 1e11

Table 1 Members and functional features of the IL-17 cytokine family. Name

Murine synonym

Human synonym

Cell source

Effector function

IL-17A/IL-17F

CTLA-8/ML-1

CTLA8

Th17, gd T cells, RORgt þ ILC, mast cells, macrophages, neutrophils, keratinocyte, iNKT

Production of IL-1b,IL-6, IL-8, IL-11, Gro-a, G-CSF and GM-CSF, antimicrobial peptide, activation of NF-kB, MAPK pathways, neutrophils

IL-17B IL-17C IL-17D IL-17E

NIRFa, CX1 CX2 / IL-25

IL-20, NIRF CX2 IL-27 IL-25

Epithelial cells

Production of antimicrobial peptides

Th17, Eosinophils, basophils

Production of IL-4, IL-5, IL-13, IgE, and eotaxin, eosinophilia, basophilia

a

NIRF-Neuronal interleukin-17-related factor.

and IL-17F share a high degree of similarity and bind the IL-17 receptor (IL-17R, a heterodimer of IL-17RA and IL-17RC subunits) [13]. IL-17A (in the literature often referred to as IL-17) was first described in 1993 [14] in human peripheral blood, as an important proinflammatory cytokine with a critical role against extracellular microorganisms and in the pathogenesis of different autoimmune diseases. Sodium chloride via the salt sensing kinase SGK1 promotes Th17 cell differentiation and autoimmunity [15,16]. Within the IL-17 family, IL-17A and IL-17F are central players in the adaptive immune response, particularly against bacteria and fungi [17,18] while the function of IL-17B, IL-17C and IL-17D is less understood [18]. Specialized Th17 cell subsets of the adaptive immune response are characterized as main sources of IL-17A in vivo and express the lineage-specific transcription factor retinoic acid receptor-related orphan receptor-gt (ROR gt), different from the Th1 and Th2 subsets. Th17 cells differentiate from naïve CD4þ T cells in the presence of IL-6 and TGFb and are subject of studies predominantly in the correlation with autoimmunity [19]. IL-1 also influences the polarization of Th17 cells [20] and innate immunity components are more likely to contribute to the first line of defense creating a bridge between innate and adaptive inflammatory components [21]. The main function of IL-17 is to induce the production of chemokines and other cytokines (such as TNFa) which recruit neutrophils and monocytes at the site of T cell activation. IL-17 also contributes to granulopoiesis by increasing the production and secretion of GM-CSF as well the expression of GM-CSF receptors. Further, IL-17 stimulates the production of antimicrobial proteins (AMP) such as LL-37 [22] and matrix remodelling proteases by neutrophils and other cells [7]. Indeed, specific innate immunity sources readily produce Th17 cytokines in different physiological and disease conditions. It has been recently demonstrated that common characteristics (such as RORg expression) can induce other lymphocytes to produce IL-17, including CD8þ ab T cells, gd T cells [23], LTi-like innate lymphoid cells (ILCs) [24], natural killer cells (NK) [25], and CD3þ invariant natural killer (iNKT) cells in mice and/or humans [26]. In addition, it is increasingly accepted that diverse innate myeloid immune cells are able to produce IL-17 and are strategically positioned in the barrier tissues, such as lungs, intestines, skin and peripheral lymph nodes to rapidly react to pathogens and allow an immediate response but also activate and amplify the adaptive immunity responses, as well illustrated by intestinal monocytes and macrophages in Crohn disease and ulcerative colitis [27,28], neutrophils in systemic vasculitis [29], mast cells in psoriatic skin lesions [22,30,31], and synovium mast cells in rheumatoid arthritis [32].

2. Innate immune IL-17-producing cells The Th1/Th2 dichotomy has been increasingly overtaken by the report that IL17-expressing T cells are a third lineage of helper T cells, coined Th17 [4,33]. Studies dedicated to IL23 and its role in autoimmunity contributed to the discovery of the Th17 cell

subset promoting chronic inflammation and tissue damage [34]. Since these earliest reports, Th17 cells received major attention and were defined as vigorously responsive to IL-1 receptor 1 (IL1R1) and IL-23 signalling, expressing the RORgt transcriptional regulator activated by IL-6-STAT3 cascade that leads to the production of IL-17A, IL-17F, IL-21, and IL22 [35]. However, IL-17 production driven by Th17 cells happens within hours after injury and cannot explain the prompt IL-17-mediated immune response and its role in rapid host defense and stress damaging responses especially in epithelial tissues [36]. Epithelia communicating with the environment, particularly the lungs, intestinal mucosa, urogenital system and skin contain most of the innate IL-17-producing cells [37]. Cells of the innate immune system producing IL-17 are illustrated in Fig. 1 and include gd T cells, invariant natural killer cells (iNKT), IL-17 innate lymphoid cells (ILC17), LTi cells (also members of ILCs), natural killer (NK) cells, mast cells, macrophages, and neutrophils. All of these cell populations manifest common and peculiar characteristics and their function is vital in maintaining tissue integrity and regulating the late immune responses [38]. For instance, ILC play a role in directing the adaptive immune response acting like sentinel cells that secrete proinflammatory cytokines TNFa, IFNg, IL-1, IL-6, IL-12, and IL-23 when challenged by the adequate stimulus. More specifically, IL-1 and IL-23 have been proven to be important in the production of IL-17 by innate immune cells such as gd T cells and iNKT cells in mouse models [39]. Macrophages and dendritic cells also secrete IL-23 in response to microbial products and inflammatory cytokines [40]. IL-23 was the first cytokine proposed to act as a mediator of the differentiation of Th17 cells as the IL-23deficient mice had reduced number of IL-17 producing CD4þ T cells compared to wild type mice [41]. Naïve murine T cells do not express IL-23R in vitro and the differentiation of Th17 cells is driven by IL-1, IL-6 and TGF-b but the expansion of Th17 cells from memory CD4þ T cells is IL-23-mediated [42]. However, several innate immune cells express the IL23 receptor, including IL-17producing gd T cells which are activated by IL-1 and IL-23 to produce IL-17A, IL-17F, IL-21 and IL-22 in the absence of TCR engagement or IL-6. Further, DCs and CD4þ cells both express IL-17R and secrete IL-23, as observed in the mouse model of multiple sclerosis [43].

2.1. gd T cells The first T cells found in the fetal thymus that provide immunity to newborns are gd T cells [44] and their proportion decreases as the development of ab T cells continues. Adult mice contain 1e4% gd T cell pool and humans 0.5e16% approximately within the total T cell population and this percentage is higher at mucosal sites [45e48]. The gd T cells are characterized by the existence of gd TCR instead of ab TCR. The generation of this receptor complex is provided by random rearrangement of genes encoded for g and d chains and sequence insertions during rearrangements but



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Fig. 1. IL17-producing innate immune cells.

manifests less diversity compared to ab TCR. Studies in mice models revealed that, similar to CD4þ T cells, gd T cells can be subdivided based on the cytokine production into subsets producing IFNg and IL-17. The expression of NK1.1 and CD27 further defines the functional phenotypes of IFNg producing gd T cells, while Scart-2 and CCR6 segregate with a commitment of IL-17 producing gd T phenotype [49,50]. On the other hand, ab T cells are primed upon antigen recognition in the peripheral lymphoid compartments, while the commitment of gd T cells takes place in the thymus and is dependent on whether gd TCR have been engaged during thymic development [51]. Ligand recognition through TCR is irrelevant for the selection process but is necessary to determine the cytokine phenotype of thymus-derived gd T cells. Following the encounter with their cognate antigen, gd T cells suppress RORgt transcriptional regulator characterizing the IL-17 program and promote T-Bet expression and IFNg production, while ligand naïve gd T cells produce IL-17 [51,52]. The TCR found on most human peripheral gd T cells is composed of the Vg9 and the Vd2 chains that are specific to recognize metabolites from different sources usually in the form of nonpeptidic phosphorylated intermediate products of the isoprenoid biosynthetic cycle [53]. Human Vg9Vd2 cells manifest a predominant terminally differentiated phenotype, CD27- CD45RA þ express granzyme B, TRAIL, FasL, CD161 and IL-17 production is mediated by the RORC transcription factor [53]. 2.2. iNKT cells Typical iNKT cells can be discriminated from other innate-like T lymphocytes subpopulations by the expression of CD1d [54] and the co-expression of a highly restricted TCR with a single invariant Va14Ja18 chain and Va24Ja18 in mice and humans, respectively, and limited TCR Vb-chains [55]. Expression of receptors such as the human NK 1.1/CD161 and NKG2D shared with NK cells are also peculiar for iNKT [56] while antigens recognized by these cells range from bacterial glycolipids (a-galacturonosylceramide, alucuronosylceramide, a-galactosyl-diacylglycerol) to mammalian iso-globotrihexosylceramide, disialoganglioside GD3, and charged

glycosphingolipids [57]. Murine spleen iNKT and human peripheral blood iNKT cells that express CD161 are able to produce IL-17 in the presence of TGF-b, IL1b, and IL23, but not IL-6 [49,58]. 2.3. Innate lymphoid cells (ILC) ILC are lineage negative (Lin-) lymphocytes generated from the postfetal liver and represent a heterogeneous group of innate immune cells which share the common transcriptional regulator ID2 and are divided in tree major subgroups depending on their functional and phenotypical characteristics. These include group 1, also referred to as NK cells (IFNg producers, T-box), group 2 (Th2 cytokine production, GATA3, RORa) and group 3 (IL-22, IL-17, includes RORgt þ ILC and LTi cells) ILC [59]. ILC from group 1 and 3 are the most prominent producers of IL-17. 2.3.1. NK cells (ILC group 1) Over the past 15 years there has been a growing interest on the functional role of NK cells in promoting resistance to infections and cancer and to modulate chronic inflammation [60]. The expression patterns of activating and inhibitory receptors as well as the IL-12Rb2 chain support the existence of multiple NK cell subsets. This view is further supported by the observations that only a portion of resting NK cells express both chains of the IL-6R, IL17þ IFN-gþ double producers are not found, and the distinct pattern of T-bet and RORgt expression in NK cells. Thus, in contrast to T cells, NK cells are considered to be preprogrammed to produce certain combinations of cytokines that provide the innate equivalent of distinct T cell subsets [61]. Following an earlier report of mouse NK cells expressing IL-17 [55], peritoneal NK1.1 þ NK cells isolated from Toxoplasma gondii-infected mice demonstrated IL17A production induced by IL-23 and IL-6 [62]. Furthermore, mucosal NK cells positively selected by NKp46 or NKp44 may be in fact linked more to LTi cells than to peripheral NK cells [63,64]. Several studies have reported that CD3e NKp46 þ cells, dependent on both RORgt and ID2 can constitutively secrete considerable amounts of IL-22 and less IFNg [26]. Whether or not these cells can rapidly produce IL-17 and/or IL-22


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remains unknown but we are convinced that human NK cells share the expression of CD56 in the absence of the CD3-TCR complex. These cells express RORgt and produce IL-22 in the digestive mucosa [65] while elevated levels of NK cells in patients with ankylosing spondylitis specifically express KIR receptors capable to recognize aberrant and correct form of HLA-B27 and secret IFNg but the correlation with IL-17 was not investigated [66,67]. 2.3.2. ILC group 3 This group of ILC includes lymphoid tissue inducers (LTi), IL-22 producing group 3 ILC, and IL-17 producing group 3 ILC. Murine LTi cells express CD4þ,CD127þ, RORgt, lymphotoxin a and b and CCR7, CXCR5 [68]. Human LTi have the same phenotype except that they do not express CD4 while the development of CD56 þ RORCþ and CD127þ NK-like cells that secrete IL-17 can be induced by LTi [69]. Murine RORgt þ LTi cells contribute to the development and maintenance of normal and inflamed lymph nodes and may migrate to the spleen [59]. IL-17 producing ILC3 release IL-17 and IFNg and are important in fungal infections [70] despite being first identified in murine bacterial-induced colitis with an increase of IL-17 and IFNg mediated by IL-23 and secreted by CD90þ,RORgtþ, Sca-1þ and IL-23R þ cells defined as ILC17 [71]. As suggested by these lines of evidence, both LTi and IL-17 producing ILC3 are particularly important in the homeostasis of the intestinal mucosa [28,72]. 2.4. Neutrophils Every early immunity battlefield story starts with neutrophils; firstly recruited at the peripheral sites of inflammation like foot solders of early response with limited proinflammatory armoury. However, it has recently become clear that neutrophils have characteristics capable of pro-inflammatory actions with wide plasticity [73,74]. Even though neutrophils are the hallmark effector cells of acute inflammation, they also contribute to chronic inflammation and adaptive immune responses in different species by product of IL-17. IL-17 secreted from neutrophils induces the release of pro-inflammatory factors (such as cytokines, chemokines and MMPs) from mesenchymal and myeloid cells, leading to the perpetuation of the recruitment and activation of additional neutrophils [75]. IL-17 production and formation of intracellular traps can be induced by IL-23 and IL1b [76] while in the ischaemia reperfusion injury model neutrophils are the major source of IL-17 and play a significant role in “sterile” inflammation [77]. 2.5. Mast cells Mast cells are resident cells found in all vascularized tissues and, upon activation, secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g. prostaglandins, leukotrienes, cytokines, chemokines, and growth factors) [78]. Nonetheless, mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergy [79], while being also implicated in a wide variety of processes that modulate inflammation. Mast cells secrete IL-17 and this is particularly noted in autoimmune diseases such as rheumatoid arthritis and psoriasis [22,32]. In particular, psoriasis inflamed skin explants is infiltrated by neutrophils and mast cells that release IL17 during extracellular trap formations (NETs) [22].

2.6. Macrophages Cells of the monocyte-macrophage lineage are important sources of IL-17 and IL-17 can also affect cells of the mononuclear phagocyte lineage. In genetically-modified mice IL-17Ra affects monocyte homeostasis and the kidney fibrotic response to injury [80] while preventing macrophage apoptosis and increasing the response to IL-10 and glucocorticoids [81]. In a separate study, IL-17 elicited a distinct transcriptional profile in mouse macrophages, contributed to monocyte attraction and adherence, while anti- IL17 antibodies prevented atherosclerotic lesion progression [82]. Chitinase-like proteins (YM1 and YM2) promote IL-17 mediated neutrophilia [83] and YM1 is the hallmark gene of IL-4 driven alternative or M2 activation of macrophages [84]. IL-17 has been shown to induce inflammation related genes in human monocytes and in vivo treatment with anti- IL-17 in psoriatic patients reduced their levels [85]. The interplay between IL-17 and cells of the monocyte-macrophage lineage deserves further analysis also in a clinical perspective. 3. Innate-derived IL-17 in the early stages of inflammation and autoimmunity The most prominent function of IL-17, whether produced by innate or adaptive immune cells, is the neutrophil chemotaxis at the site of infection which is necessary for microorganism clearance [86], mediated by the production of CXC chemokines, including IL-8 (CXCL8) and growth-regulated oncogene-alpha (GROa, CXCL1), and growth factors, including granulocyte colonystimulating factor (G-CSF) and granulocyte macrophage colonystimulating factor (GM-CSF), antimicrobial proteins such as bdefensin-2, mucins (MUC5AC and MUC5B) [87,88], and S100 proteins from epithelial cells and smooth muscle cells, as well as fibroblasts. As previously mentioned, cytokines of the IL-17 family bind to IL-17R that is widely expressed on different cell types; this interaction leads to the secretion of granulocyte-colonystimulating factor (G-CSF) and organ-specific chemokines that promote neutrophil recruitment from the circulation. Synergy of IL-17 with other proinflammatory cytokines such as IL-1, IL-6 and TNFa further results in neutrophil activation [89]. Neutrophil recruitment, however, is not the only IL-17 action as this cytokine family exerts pleiotropic effects with IL-17A, IL-17C and IL-17F directly targeting tissue epithelial cells to induce various antimicrobial responses against extracellular pathogens and promote tissue remodelling [90]. On the other hand, IL-17E primarily acts on leukocytes and induces a Th2 response that is crucial for protection against extracellular microbes [91] and negatively regulates IL-17A/IL-17F production from leukocytes [92]. IL-17A/F stimulates macrophages to produce the inflammatory cytokines IL-1b and TNFa and act synergistically with TNFa in IL-6 and GM-CSF production from fibroblasts [18,93]. IL-17A/F is involved in limiting infection spreading by promoting expression of proteins that maintain epithelial integrity [94]. In the gut epithelium IL-17A/F stimulate the secretion of claudin 1 and claudin 2 which are involved in the formation of tight junction between cells ultimately forming a large, interconnecting network and maintaining intestinal integrity [94,95]. IL-17A/F can also induce inflammatory mediators such as matrix metalloproteinases (MMP) that can cause tissue damage by proteolytic degeneration of collagens and proteoglycans, a phenomenon of great importance in the cartilage destruction observed in rheumatoid arthritis [96] with its complex etiopathogenesis [97,98]. Further, IL-17A/F induces the expression of RANKL by osteoblasts that mediates osteoclastogenesis, leading to bone erosions [99]. In intestinal inflammation, IL-17A/F also stimulates



MMP, IL6, and IL-8 production from cultured colonic sub-epithelial myofibroblasts [100]. In the central nervous system, IL-17A/F disrupts the bloodebrain barrier tight junction, which facilitates the local migration of CD4þ T cells [101]. IL17A/F produced by gd T cells acts directly on CD4þ T cells but also via IL-17R signalling on antigen presenting cells enhance the production of IL23 and other Th17 cell-promoting cytokines and chemokines that suggest possible role of IL17 A/F in amplifying Th17 responses and exacerbating autoimmune disease [43]. Evidence cumulatively supports a significant involvement of IL-17A/F in the pathogenesis of tissuespecific and systemic autoimmune diseases [102]. While most of our understanding of the IL-17 cytokines is based on IL17A and F, data are being provided more recently on other members of this family. IL-17C preferentially targets epithelial cells and triggers proinflammatory pathways similar to IL-17A/F (including neutrophil chemoattractants, proinflammatory cytokines and antimicrobial peptides) and exerts a protective role in the immune response to bacterial infections. Major differences include the observation that IL17 receptor E expression is limited and IL-17C is less potent than IL-17A/F. Recent data support a role for IL-17C in mediating the Th17 response as IL-17RE expression is upregulated in Th17 [76]. 4. Innate-derived IL17 in chronic inflammation and autoimmunity Most evidence on IL-17-producing innate immune cells in the perpetuation of chronic inflammatory and autoimmune disorders is derived from rheumatoid arthritis [103] and psoriatic disease [104,105], including both skin psoriasis and psoriatic arthritis, two complex conditions in which IL-17 targeting is at an advanced development stage, as will be discussed in further details, and may provide treatment options that are not common to both conditions as for currently available TNFa inhibitors [106]. In the murine collagen-induced arthritis (CIA, a model of rheumatoid arthritis) IL-17 is produced by gd T cells and CD4þ T cells [107,108] found in the peripheral blood but not the affected joints [109]. Innate immune cells in the CIA mice are not sufficient to induce disease but play a pivotal role triggered by production of IL-23 that affects innate cells as well Th17 cells. The depletion of gd T cells (Vg4þ subset of gd T cells) during CIA results in less severe disease and IL-17 production from gd T cells is critical in the development of CIA along with Vg4þ gd T cells [110]. Interestingly, the increase in gd T cell numbers is antigen-independent and likely due to the response to complete Freund's adjuvants (CFA) as the numbers of gd T cells in the arthritic lesions were similar with or without antigen provided the CFA is present [107,111]. On the other hand, human studies demonstrate that Th17 cells are relatively rare in rheumatoid arthritis synovium [109] and mast cells have highest expression of IL-17A in humans synovium affected by rheumatoid arthritis. The factors that might drive synovial mast cell IL-17A expression can include complement factors, immune complexes, cytokines, and TLR ligands[32]. The pathogenesis and aetiology of psoriatic disease remain under scrutiny, with numerous theories that include contribution of every single cell type causing dysregulated inflammatory process leading to the characteristic histopathological psoriasis picture [112]. At the earliest phases of disease, the skin manifestations include hyperkeratosis and silvery-white scales due to hyperproliferating keratinocytes, and epidermal keratinocytes were thought to be major players [113]. Other pathogenetic hypotheses involve neutrophils, mast cells, endothelial cells, dendritic cells, and ultimately T cells. The observation that psoriasis is a uniquely human disease is a major obstacle to develop a comprehensive

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animal model even although several were proposed in recent years [114]. Innate immune cells (particularly mast cells and neutrophils) but not T cells are the major cell types for IL-17 production in the human skin. Indeed, IL-17 þ mast cells are present in psoriasis plaques but also in atherosclerotic plaques suggesting that IL-17 secreted by mast cells may contribute to the cardiovascular changes associated with severe psoriasis. Psoriatic arthritis is the chronic inflammatory joint disease appearing in 30% of patients with skin psoriasis. As previously discussed, mast cells predominantly release IL-17 in the inflamed synovia of rheumatoid arthritis and may also contribute to the mast cells-mediated IL-17 production in psoriatic arthritis [115]. Th17 cells are increased in the circulation of patients with psoriatic arthritis, and exhibit a highly differentiated and polyfunctional phenotype. Th17 and c-Kit positive mast cells are increased in the synovial fluid of patients with psoriatic arthritis and synovial fibroblasts in vitro produce high levels of IL-17 and IL17R compared to osteoarthritis [116,117]. In the murine model of aldara-induced psoriasis, Th17 cytokines IL-17A, IL-17F and IL-22 produced by skin-invading population of gd T cells and RORgt CD3-innate lymphocytes are of key importance [118]. IL-1R8, also known as SIGIRR or TIR8 [20] is a negative signalling regulator of the IL-1 receptor family and is down regulated in the peripheral blood leukocytes of psoriatic patients [119]. IL-1R8 is a negative regulator of Th17 differentiation [20] and IL-1R8 deficiency is associated with an increased Th17-driven antifungal murine response [120] while acting as a key brake of IL-1-driven Th17 differentiation [120,121]. In a model of psoriasis, IL-1R8deficient mice were found to be more susceptible to the development of the disease while the major source of IL-17 under these conditions was gd T cells [122]. Other authors observed a significant correlation between the number of Th17 cells in peripheral blood and disease severity in different animal models of psoriasis-like skin inflammation with mast cells and neutrophils as the major cell types expressing IL-17. However, human mast cells do not contain IL-17A but rather express the less potent IL-17F [123] and limited data support the existence of IL17 gd T cells in the human skin. Dermal gd T cells are increased greatly compared to healthy controls and significantly reduced in the circulation, indicating redistribution of the cells from the blood to the skin compartment [112]. In human psoriatic skin, an overall increase of dendritic cells has been found both in the epidermis and in the dermis. Dendritic cell types that are normally absent in healthy skin, such as TNF and iNOS-producing DCs (Tip-DC), slanDC, and plasmacytoid DC (pDC), have been shown to infiltrate predominantly the dermal compartment of psoriatic skin [124] and dendritic cells are an important source of IL-23 [31]. The resident epidermal ILC were dramatically decreased within psoriatic plaques compared to the healthy skin [30]. NKp44 þ ILC3 cells are increased in the peripheral blood and skin in psoriasis and produce IL-17A [30]. No significant changes are noted in the peripheral blood population of T, B, NK cells, and myeloid cells between healthy individuals and patients with psoriatic disease. The increase of this particular subset of ILCs is present in the unaffected skin areas of psoriatic patients and suggests these may not be simply recruited in the skin following T cell activation [30]. IL-17 produced by neutrophils and mast cells also has been shown to be critical for neutrophil accumulation [22]. 4.1. IL-17 and infections Bacteria, fungi, viruses and parasites share the capacity to induce a major production of IL-17 during the early innate response [70,125,126]. IL-17A can be largely produced by nonconventional murine T cells, as first demonstrated in the pulmonary


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Mycobacterium tuberculosis infection; in this model the early secretion of IL-23 induces the production of IL-17A by gd T cell while dendritic cells produce IL-23 and trigger IL-17 secretion by gd T cells [127,128]. On the other hand, the mycobacterial granulomas are facilitated by IL-17A producing gd T cells that enhance expression of adhesive molecules ICAM-1 and LFA-1 leading to chemotaxis towards granulomas [129,130]. In the murine model of pulmonary Nocardia infection the bacterial clearance of infected tissues and host survival are highly dependent on the action of neutrophils and gd T-lymphocytes [130,131]. The interplay between IL-17 and CXC chemokines can be further explained by a neurostat feedback loop that induces the production of G-CSF, which in turn initiates CXC chemokine production that directly promotes neutrophil trafficking and protective immunity [130]. IL-17 is produced locally in lung tissues as part of the early host response to a bacterial challenge with the Nocardia asteroides strain GUH-2. The direct contribution of IL-17 remains to be clarified during chronic infections; similarly, IL-17þ gd T-lymphocytes appear to directly impact CXC chemokines, which also strongly influence neutrophil trafficking and host sensitivity to Nocardia infection [130]. During acute pulmonary inflammation caused by Pseudomonas aeruginosa in mice, the early production of IL-17 plays protective role and gd T cells are major producers of IL-17 and play a pivotal role in the host defense against bacterial infections [131]. Local infiltration of neutrophils is one of the earliest events induces by bacterial infection with Escherichia coli. The entry of bacterial colonies in the intraperitoneal cavity in mouse model leads to the production of IL-17A by gd T cells as a major source, attracting neutrophils [132]. The immune response against mouse skin infections by Staphylococcus aureus is mediated by the interplay between activated neutrophils and abscess formation which are required for bacterial clearance [133]; resident epidermal gd T cells allow neutrophil infiltration via the IL-1, TLR2, and IL-23ederived production of IL17. Similarly, the mouse liver intracellular infection with Listeria monocytogenes activates an early protective response mediated by gd T cells and the production of IL-17A. IL-17A enhances the antibacterial activity of L. monocytogenes-infected non-phagocytic cells, which correlate with the induction of antimicrobial peptide mouse beta-defensin gene expression [134,135]. IL-17 also plays important roles in early response during fungal infection. Neutrophils and CD4þ T cells (supposed Th17 cells) are the main producers of IL-17 during Candida keratitis [136] while the neutralization of IL-17A and IL-17F, which appear to have redundant roles during the course of oropharyngeal candidiasis, causes a severe disease associated with defective weight recovery and fungal clearance. IL-17producing ILC (characterized by the CD45þ, CD90þ, Sca-, CD127 þ phenotype) take central stage when immediate defence in the oral mucosa is most needed to confine the invading pathogens [70]. As mentioned above, IL-1R8 is a negative regulator of IL-17 in fungal infection [120]. The liver lymphocyte milieu that is specific per se induces an early production of IL-17A by gd T-cells but also by other intrahepatic lymphocytes in combating adenovirus acute infections which ultimately lead to a full CD8þ and CD4þ T cell response [137]. In the case of parasites, data on the murine intraperitoneal infection by T. gondii suggest that neutrophils are key players [55] and IL-17A leads to accessory cell production of IL-6 and IL-23, two cytokines related to IL-12, which in combination with TGF-b promote IL-17 production by a distinct population of NK cells [62]. Human data on IL-17 in chronic and acute infections are significantly less advanced. First, Peng and Colleagues demonstrated an increase of human IL-17-producing gdT cells in the peripheral blood of patients with active pulmonary tuberculosis [138] while others demonstrated elevated levels of IL-17 in cerebrospinal

fluids of children affected with bacterial meningitis. In addition, IL-17 þ cells are the predominant Vg9Vd2 T-cell population from the cerebrospinal fluids of these patients [139]. The IL-17þ Vg9Vd2 T lymphocytes isolated from the peripheral blood of children with bacterial meningitis express CD45RA, CD161, CCR6, and TRAIL but not CD27 and perforin, thus matching the phenotype of in vitro differentiated IL-17þ Vg9Vd2 T cells [139]. Interestingly, Bermejo et al. reported that B cells are the major source of IL-17 after the infection with the extracellular parasite T. cruzi and that B cells produce IL-17 in a RORgt-independent way [126].

4.2. IL17-targeting therapies in psoriatic disease Whether IL-17 is predominantly produced by innate cells or Th17 adaptive cells does not change the central role of this cytokine in the pathology of psoriasis and psoriatic arthritis which is largely addressed elsewhere [140,141]. Anti-IL17 agents are rapidly becoming important therapeutic tools in these conditions and are currently in advanced development stages. In the pipeline of new biologic drugs which are summarized in Table 2, three agents targeting the IL-17 signalling are being tested for the treatment of psoriatic disease: i.e. brodalumab, ixekizumab, and secukinumab. Brodalumab is an IL17-receptor antagonist while ixekizumab and secukinumab both neutralize IL17 and differ in the fact that secukinumab is a fully human and ixekizumab a humanized monoclonal antibody [142,143]. The therapeutic potential of secukinumab was suggested in several autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, and noninfectious uveitis [7,144]. Due to the IL-17 protective role in early response against environmental pathogens, its impaired function can lead to recurrent infections [145,146] but data from clinical trials do not report significantly increased risks of infections [147]. Different from psoriatic arthritis, secukinumab did not succeed in a short randomized controlled trial in rheumatoid arthritis [148,149] while ixekizumab was evaluated in patients with rheumatoid arthritis on a stable dose of DMARDs and anti-TNF-a with inadequate response and showed efficacy in all treatment groups compared with placebo [150]. A subsequent follow-up trial showed significant dose-related improvement in rheumatoid arthritis symptoms in both groups [151]. Ixekizumab is now undergoing a Phase III trial in rheumatoid arthritis but its development is more focused on psoriasis and psoriatic arthritis. The use of brodalumab in one study was associated with a 77% prevalence of side effects in patients with rheumatoid arthritis [152]; in this study effectiveness was not the primary endpoint but brodalumab did not show any clinical improvement when compared to placebo. Similarly to secukinumab and ixekizumab, the development for brodalumab is more focused on psoriasis and psoriatic arthritis. In the case of psoriatic disease, secukinumab achieved significant effectiveness in Phase II studies on moderate and severe plaque psoriasis that led study in the phase III. Recently, two successfully completed clinical trials have been published on secukinumab in psoriasis [153]. In the case of PsA, phase III clinical trials are ongoing due to rapid clinical, serological and life improvements even if secukinumab did not reach the primary objective in one phase II trial [154]. Phase II clinical studies showed good response in the treatment of psoriasis with ixekizumab and paved the way for designing ongoing phase III trials. Subcutaneously administrated ixekizumab showed improving response rates in psoriatic arthritis and psoriasis in a phase II study [155]. Brodalumab showed similar efficiency in improving psoriatic arthritis severity at two different dosage (140 and 280 mg) two times a month compared to placebo group as well in phase II of clinical study while phase III studies are ongoing [156].


N. Isailovic et al. / Journal of Autoimmunity xxx (2015) 1e11 Table 2 Biologics targeting the Th17 pathway in the pharmaceutical pipeline. Biologic

Antibody type

Disease, ongoing study phase

Efficacy

Brodalumab

human IgG2 anti-IL-17RA monoclonal antibody humanized IgG4 monoclonal antibody targeting IL-17A

psoriasis, phase II [161] psoriatic arthritis, phase II [156] rheumatoid arthritis, phase II [151]

Improvement of PASI-75a in up to 82% of patients and of quality of life PASI-75 in early phase of study showed improvement ranging from 45 to 82% in the study population in different dose clinical trials Improvement in signs and symptoms in patients who were either naive to biologics treatment or had an inadequate response to TNF inhibitors. No unexpected safety concerns. A high proportion of patients responded to ixekizumab therapy and maintained clinical responses over 1 year of treatment with dose-dependent PASI-75 rates ranging from 77% to 82% with no unexpected safety signals. Over 80% of patients in different dose group achieved PASI 75. There were no serious adverse events. Only patients in highest dose group had a significant decrease in joint pain compared to placebo. Patients who failed to respond to DMARD and other biologics showed an improvement (ACR50b, DAS28, CRP) with 150 mg of secukinumab. PASI-75 dose dependent and ranging from 42 to 87% of patients reduction in joint pain and PASI-75 score improvement in 77% of patients.

Ixekizumab

psoriasis, phase II [162]

psoriatic arthritis, phase II

Secukinumab

fully human IgG1k IL-17A specific monoclonal antibody

rheumatoid arthritis, phase II [149] psoriasis, phase III [163,164] psoriatic arthritis, phase III [163] ankylosing spondylitis, phase III [163] non infectious uveitis, phase II multiple sclerosis, phase II [163]

Ustekinumab

Tildrakizumab

Guselkumab

ABT-122

AMG 139

fully human IgG1k IL-12 ep40 and IL-23ep40 specific monoclonal antibody

fully human IL-23ep19 specific monoclonal antibodies fully human IL-23ep19 specific monoclonal antibodies

Dual-variable-domain immunoglobulin IL-17A and TNF-a specific fully human IL-23ep19 specific antibody

BI 655066

humanized IL-23ep19 specific antibody

CNTO 6785

fully human IL-17A specific antibody IL-17A specific antibody Bispecific fusion protein antibody targeting IL-17 and TNF-a

CJM112 COVA322

ALX-0761

Bimekizumab

SCH-900117 a b c

Bispecific half-lifeextended nanobody specific for IL-17A/F Humanized bispecific IL17A and IL-17F monoclonal antibody fully human IL-17A specific monoclonal antibody

rheumatoid arthritis, phase II psoriasis (marketed) [164,165] psoriatic arthritis (marketed) [164]

Crohn's disease, phase IIB [166] psoriasis, phase IIB [167]

rheumatoid arthritis, phase II

psoriasis, phase IIB [167] psoriatic arthritis, phase II [167] rheumatoid arthritis, phase II psoriatic arthritis, phase II psoriasis, phase I

patients who had active disease despite previously treatments secukinumab administration intravenously or subcutaneously acheived ASAS20c response in >60% of cases. improvement in visual acuity, reduction in ocular inflammation in 13e25% of patients In relapsing-remitting multiple sclerosis secukinumab was associated with a 67% reduction of new gadolinium-enhancing lesions which are a marker of disease. ACR20 in >50% of subjects with improvement in DAS28 value as well. PASI-75 response was achieved at week 52 in 43e48% of patients weighing 100 kg in a dose-dependent manner. Improvements of ACR20 response rates; at maximal efficacy ACR20 was achieved in dose-depending ranging from 33 to 37% of study population. PASI75 was achieved in 40e57% of patients. Trend of percentages was constant until end of the study. Clinical response was improved in diverse dose-dependent groups in 27e47% patients; significant decrease in CRP PASI-75 in 78% of subjects. No specific pattern of adverse events.

Ustekinumab and guselkumab are currently being compared in combination with methotrexate in an ongoing Phase study (the study has completed recruitment) in patients with active moderate to severe RA who have had inadequate response to methotrexate. PASI-75 in 66% of patients over time. ongoing study ongoing study ongoing study PASI-90 or 100 was reached by Day 85e113 and fewer differentially regulated genes were observed between lesional and nonlesional tissues vs placebo. decreases in CDAI, serum CRP, and fecal calprotectin. PASI-75 at 12 and 24 weeks in 87% and 71% of patients ongoing study

Crohn's disease, phase II psoriasis, phase II [168] Ankylosing spondylitis, phase II Crohn's disease, phase II rheumatoid arthritis, phase II

ongoing study ongoing study

psoriasis, phase I/II rheumatoid arthritis psoriasis, phase I/II psoriatic arthritis, Ankylosing spondylitis, psoriasis, phase Ib

ongoing study preclinical studies ongoing study preclinical studies preclinical studies ongoing study

psoriasis; psoriatic arthritis phase I

ongoing study

rheumatoid arthritis, phase I

ongoing study

PASI-75/90 Psoriasis Area Severity Index score improvement for 75%/90. ACR 20/50 American College of Rheumatology improvement for 20/50%. ASAS Assessment of Spondyloarthritis score improvement for 20%.


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5. Concluding remarks Cytokines of the IL-17 family are important pro-inflammatory players in the cytokine network created both by innate and adaptive immunity cells and this complex network is central to an adequate inflammatory response. Indeed, the current evidence supports the fascinating view that members of this family act as a bridge between early and late immune responses, particularly in mucosal sites such as the gastrointestinal tract or the skin. Nonetheless IL-17 remains the crossroad of controversial studies on its protective role in early infections by different bacterial, fungal and parasite invasion in acute immune responses but also its prominent involvement in the pathogenesis of chronic inflammatory and autoimmune diseases. We herein discussed the growing evidence supporting that innate immune cells are prominent producers of IL-17 and we are convinced that this observation will rapidly become of major importance provided that new drugs targeting IL-17 are becoming available and personalized medicine will be the target for complex immunemediated diseases [105,157,158]. Ultimately, whether IL-17 is produced by innate immunity cells such as unconventional T cells, members of ILC recently described population of innate cells, neutrophils and mast cells or Th17 adaptive immunity cells may hold important keys to the tissue specific response to these treatments and possibly personalized medicine in chronic inflammatory diseases, similar to what has been observed in rheumatoid arthritis [159,160]. Acknowledgements Novartis, Italy, provided unconditional support for editorial assistance. References [1] R. Medzhitov, C. Janeway Jr., Innate immunity, N. Engl. J. Med. 343 (2000) 338e344. [2] C.A. Feghali, T.M. Wright, Cytokines in acute and chronic inflammation, Front. Biosci. 2 (1997) d12e26. [3] A. Awasthi, V.K. Kuchroo, Th17 cells: from precursors to players in inflammation and infection, Int. Immunol. 21 (2009) 489e498. [4] T.R. Mosmann, R.L. Coffman, TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties, Annu Rev. Immunol. 7 (1989) 145e173. [5] G. Del Prete, Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy, Allergy 47 (1992) 450e455. [6] J.W. Steinke, L. Borish, Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists, Respir. Res. 2 (2001) 66e70. [7] W. Hueber, D.D. Patel, T. Dryja, A.M. Wright, I. Koroleva, G. Bruin, et al., Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis, Sci. Transl. Med. 2 (2010) 52ra72. [8] E. Schmitt, M. Klein, T. Bopp, Th9 cells, new players in adaptive immunity, Trends Immunol. 35 (2014) 61e68. [9] T. Korn, E. Bettelli, M. Oukka, V.K. Kuchroo, IL-17 and Th17 cells, Annu. Rev. Immunol. 27 (2009) 485e517. [10] S. Eyerich, K. Eyerich, D. Pennino, T. Carbone, F. Nasorri, S. Pallotta, et al., Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling, J. Clin. Investigation 119 (2009) 3573e3585. [11] J.J. O'Shea, W.E. Paul, Mechanisms underlying lineage commitment and plasticity of helper CD4þ T cells, Science (New York, NY) 327 (2010) 1098e1102. [12] J. Zhu, H. Yamane, W.E. Paul, Differentiation of effector CD4 T cell populations (*), Annu. Rev. Immunol. 28 (2010) 445e489. [13] C. Gu, L. Wu, X. Li, IL-17 family: cytokines, receptors and signaling, Cytokine 64 (2013) 477e485. [14] E. Rouvier, M.F. Luciani, M.G. Mattei, F. Denizot, P. Golstein, CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene, J. Immunol. 150 (1993) 5445e5456. [15] C. Wu, N. Yosef, T. Thalhamer, C. Zhu, S. Xiao, Y. Kishi, et al., Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1, Nature 496 (2013) 513e517.

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Cholesterol, inflammation and innate immunity.

NASH.

Innate lymphoid cells in inflammation and immunity.

Homeostatic inflammation in innate immunity.

Mitochondrial Control of Innate Immunity and Inflammation.

Heme on innate immunity and inflammation.

IAPs, regulators of innate immunity and inflammation.

Innate immunity against Leishmania infections.

The dual role of nod-like receptors in mucosal innate immunity and chronic intestinal inflammation.

Understanding innate immunity and inflammation in acne: implications for management.

Autophagy, inflammation and innate immunity in inflammatory myopathies.

Biomarkers of inflammation and innate immunity in atrophic nonunion fracture.

Suppression of innate inflammation and immunity by interleukin-37.

AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity.

Innate immunity and inflammation of the bovine female reproductive tract in health and disease.

More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation.

Differential expression of innate immunity genes in chronic rhinosinusitis.

Direct-Acting Antivirals Cure Innate Immunity in Chronic Hepatitis C.

Innate Immunity and Breast Milk.

The Epitranscriptome and Innate Immunity.

Trained innate immunity and atherosclerosis.

Innate immunity.

Chronic lung inflammation primes humoral immunity and augments antipneumococcal resistance.

Innate and Adaptive Immunity Synergize to Trigger Inflammation in the Mammary Gland.