Monocyte and macrophage plasticity in tissue repair and regeneration.

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The American Journal of Pathology, Vol. -, No. -, - 2015

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Regenerative Medicine Theme Issue

REVIEW Monocyte and Macrophage Plasticity in Tissue Repair and Regeneration Q24

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Amitava Das, Mithun Sinha, Soma Datta, Motaz Abas, Scott Chaffee, Chandan K. Sen, and Sashwati Roy From the Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, The Ohio State University Wexner Medical Center, Columbus, Ohio Accepted for publication June 11, 2015.

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Address correspondence to Sashwati Roy, Ph.D., The Ohio State University Medical Center, 473 W 12th Ave, 511 DHLRI, Columbus, OH 43210. E-mail: sashwati. [email protected].

Cells of the monocyte-macrophage lineage are highly versatile and heterogeneous. The mononuclear phagocyte system has been defined as a hematopoietic cell lineage derived from progenitor cells in the bone marrow. The mononuclear phagocyte system is composed of three major cells types: monocytes, macrophages, and dendritic cells. Although monocyte heterogeneity is not fully understood, it is suggested that monocytes continue to develop and mature in the blood, and they can be recruited to the tissues at various points during this maturation continuum. In regenerative tissue, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable. Macrophages are highly plastic cells. On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory (M1) or anti-inflammatory or proreparative (M2) phenotypes and transdifferentiate into other cell types. Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs. (Am J Pathol 2015, -: 1e11; http://dx.doi.org/ 10.1016/j.ajpath.2015.06.001)

The concept of cell plasticity originated from the ability of adult stem cells to differentiate into multiple cell types. Heterogeneity and plasticity are hallmarks of cells of the monocytemacrophage lineage.1 It has been recognized that in response to the cues from the microenvironment, monocytes and macrophages have the ability to undergo phenotypic and functional switch. In addition to switching between polarization states, these cells may transdifferentiate into endothelial or other cells in vitro and in vivo. In the current review, we focus on the heterogeneity and plasticity of monocytes and macrophages. The plasticity of macrophages plays a decisive role in tissue repair and regeneration. Herein, we discuss the current known mechanisms, including the roles of microenvironmental cues and molecular mediators, such as noncoding RNAs underlying the plasticity and differentiation of macrophages in tissue repair and regeneration.

MPS Data The mononuclear phagocyte system (MPS) is composed of three major cell types: monocytes, macrophages, and dendritic

cells (DCs). As a result of phenotypic and functional overlaps, the precise boundaries defining these groups are not clear.2 MPS has been defined as a hematopoietic cell lineage derived from progenitor cells in the bone marrow. These cells differentiate and enter the systemic circulation to form monocytes, and then infiltrate into tissues to become macrophages.3 The other cells of MPS (ie, DCs and macrophages) also have a remarkable heterogeneity related to their origin, phenotype, tissue localization, proliferative potential, and function.4 Cells of MPS are extremely plastic in their gene expression patterns, thus defying identification on the basis of surface markers.5 The proliferation and differentiation of MPS cells is controlled by macrophage colony-stimulating factor (CSF)-1 and IL-34, Q6 Supported by National Institute of Diabetes and Digestive and Kidney Q2 Diseases grant R01 DK076566 (S.R.), National Institute of Nursing Research grants NR015676 (S.R.) and NR013898 and NR015676 (C.K.S.), and National Institute of General Medical Sciences grants RO1 GM108014, GM069589, and GM 077185 (C.K.S.). Q3 A.D. and M.S. contributed equally to this work. Disclosures: None declared. This article is part of a review series on regenerative medicine.

Copyright ª 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2015.06.001

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Figure 1 Origin and development of the mononuclear phagocyte system. Hematopoietic stem cells (HSCs) in fetal liver or adult bone marrow develop into a progenitor of both macrophages and granulocytes. The granulocytemacrophage colony-forming unit (GM-CFU) population can commit to the macrophage colonyforming unit (M-CFU) or the granulocyte CFU group of cells. Before becoming macrophages, the M-CFU differentiates into monoblasts, promonocytes, and mature monocytes. This process requires the growth factor colony-stimulating factor-1. In mice, Ly6C is a marker for an inflammatory population of monocytes. In humans, the corresponding marker is CD16.

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125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 acting through a common receptor, CSF-1 receptor.6 Hemato148 poietic stem and progenitor cells can circulate and proliferate 149 inside extramedullary tissues and produce tissue-resident 150 151 myeloid cells, especially DCs.7 Thus, the MPS may not only 152 be a family of monocyte-derived cells, but also a more complex 153 cellular system involved in the scavenging of dying cells, 154 pathogens, and molecules via a variety of cellular processes.8 155 156 157 Origin, Function, and Heterogeneity 158 159 Monocytes 160 161 Monocytes represent 10% of leukocytes in human blood and 162 4% of leukocytes in mouse blood. Monocytes play an 163 important role in development, homeostasis, and inflamma164 tion, in part via the removal of apoptotic cells and scavenging 165 of toxic compounds.9 Monocytes originate in the bone 166 marrow from hematopoietic stem cells and develop through a 167 series of sequential differentiating stages to produce mono168 blasts, promonocytes, and, finally, monocytes, which are 169 released from the bone marrow into the bloodstream 170 171 ½F1 (Figure 1).10 Although monocyte heterogeneity is not fully 172 understood, it is suggested that monocytes continue to 173 develop and mature in the blood and can be recruited to the 174 tissues at various points during this maturation continuum. 175 The point at which they start their journey from blood may 176 define their functions.11 177 In mice, two populations of monocytes have been identified 178 and named as inflammatory and patrolling monocytes, 179 depending on the time they spend in the blood before migrating 180 12 to tissues. In humans, a new nomenclature on the basis of the 181 expression of surface markers CD14 and CD16 has been 182 183 recently approved by the Committee of the International Union 184 of Immunological Societies. According to this new system, the 185 monocyte population has been divided into three subsets: i) the 186

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major population of human monocytes (90%) with high CD14 but no CD16 expression (CD14þCD16; alias classic monocytes), ii) the intermediate subset (CD14þCD16þ), and iii) the low CD14- but high CD16-expressing or nonclassic subset (CD14dimCD16þ).13 The physiological role of the monocyte subsets in vivo is not fully defined. In general terms, both human classic and intermediate monocyte subsets have inflammatory properties (inflammatory monocytes), whereas the nonclassic monocyte subset displays patrolling (crawling) behavior along vessel walls and reacts strongly against viruses. The inflammatory monocytes are highly plastic and modify their phenotype to the requirements of the specific environment and/or pathogenspecific immune responses.14 Although controversial, some studies indicate that the inflammatory monocytes are essentially precursors of the patrolling subset under steady-state conditions and that this conversion can occur either in the bone marrow or within the blood.14 A rare subset of monocytes is known to express TIE2, the receptor for angiopoietins, and is therefore termed TIE2expressing monocytes.15 The TIE2-expressing monocytes and intermediate (CD14þCD16þ) subsets of monocytes with high angiogenic potential have been associated with liver regeneration.15 Another example of involvement of monocytes in tissue regeneration is based on the observation that the osteoclasts of the regenerating salamander limb form by fusion of monocytes.16 These studies suggest involvement of specific subsets of monocytes in the tissue regeneration process.

DCs DCs are essential mediators of innate and adaptive immune responses.17 Relative to other cells of MPS, our understanding of the molecular mechanisms that regulate the development of DCs is limited. DCs are composed of distinct subsets for which

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Macrophage Plasticity 311 312 Tissues/organs Name of cells Major functions 313 Wound Wound macrophages Scavenging,39 phagocytosis,38 efferocytosis,40 antigen presentation,46 promotion of 314 repair,39,43 extracellular signaling,35 and angiogenesis43,49 315 Central nervous system Microglial cells Scavenging,36 phagocytosis,42 cytotoxicity,37 antigen presentation,31 synaptic 316 stripping,32 promotion of repair,45 and extracellular signaling44 317 Lungs Alveolar macrophages Efferocytosis,47 phagocytosis,48 and surfactant homeostasis51 318 Connective tissue Histiocytes Phagocytosis34 and antigen presentation34 319 Liver Kupffer cells Endocytic activity against blood-borne materials entering the liver33 and host defense41 320 Bone Osteoclasts Bone resorption50 321 322 323 324 precise functions and interrelationships remain to be elucidated. Although macrophages in tissues have many features in 325 The advances in establishing classic DCs as a distinct lineage common, they are nevertheless extremely heterogeneous in 326 among myeloid cells and their function in vivo have been terms of function and surface marker expression30 17 31e51 recently reviewed. Because of relative rarity and phenotypic (Table 1). The anatomical location of the macrophages ½T1 327 328 similarity to other cells of the PMS, their role in wound healing dictates their heterogeneity in terms of their function.10 In the 329 is not well described. Among DCs, the plasmacytoid DCs, white adipose tissue, the number and the activation state of the 330 which are normally absent from healthy skin, have been shown macrophages determine the metabolic health of adipocytes, 331 to rapidly infiltrate skin wounds with quick kinetics, paralleling which, in turn, regulate the metabolism in the white adipose 332 the infiltration of neutrophils.18 Whether such infiltration of tissue through the release of hormones called adipokines.52,53 333 plasmacytoid DCs in wounds is a general occurrence or is Macrophages present in the brown adipose tissue are required 334 associated with conditions such as infection remains to be to enable the metabolic acclimatization to cold.54 The resident 335 336 tested. Plasmacytoid DCs are a rare population of circulating macrophages of the liver (alias Kupffer cells) comprise the 337 cells that produce large quantities of type I interferons (IFNs) in largest section of tissue macrophages in the body55 that 338 response to viral infections.19 expedite the metabolic adaptations of hepatocytes during high 54 339 caloric intake. Alveolar macrophages in the lungs phago340 cytose any potentially harmful pathogen that is taken in from 341 56 Macrophages the air during respiration. Interestingly, the cervical region 342 consists of both M1 and M2 phenotypes (discussed later), 343 Origin, Functions, and Steady-State Tissue Distribution which are possibly responsible for the postpartum repair of 344 tissue. However, increased mRNA expression of CSF-1 345 Considered to be important immune effector cells of the receptor and other markers of M2 macrophages during labor 346 innate immune system, macrophages not only provide the or shortly postpartum suggests a role of M2 macrophages in 347 first line of defense against microorganisms but also initiate 57 20 348 postpartum tissue repair. Macrophages abundantly present in and control the adaptive immune responses. Ilya Mech58 349 tumors are called tumor-associated macrophages (TAMs). nikov, a Russian-French biologist, discovered in 1884 that 350 Unlike the other tissue-resident macrophages, TAMs reprecertain white blood cells engulf and digest bacteria by a 58 351 sent more of an M2 phenotype. M2-like TAMs in estabprocess that he referred to as phagocytosis, and the cells 352 lished tumors endorse tumor-induced immunosuppression, were named macrophages (derived from the Greek words 353 21 suggesting a switch of macrophage phenotype from M1 makros, big eaters, and phagein, eat). Apart from being 354 during tumor onset to M2 in established tumors.59e61 involved in producing required growth factors, macrophages 355 also play an important role in tissue repair, remodeling, and 356 357 synchronizing metabolic functions.22,23 Macrophages effiPlasticity and Polarization 358 ciently clear apoptotic polymorphonuclear leukocytes, a 359 prerequisite for a favorable resolution of inflammation,24 by Macrophages and their activation states are characterized by 360 efferocytosis (phagocytosis of apoptotic cells).25 A dysreplasticity and flexibility.20,58,62 Depending on the environ361 gulation in macrophage efferocytosis may lead to autoimmental stimuli, macrophages have a wide array of functions, 362 26 munity and persistent inflammatory diseases. especially in the modulation of innate immune response 363 63 through the release of several factors. In fact, some of these Circulating blood monocytes were believed to be the 364 27 exclusive precursors of tissue macrophages. Monocytes activities of macrophages are opposing. The diverse roles (ie, 365 proinflammatory or anti-inflammatory nature of macrophages derived from the bone marrow differentiate to macrophages in 366 in immune responses) depend on the environmental stimuli the intestine and the dermis during acute infection and 367 that induce the macrophages to acquire a distinct functional inflammation.28 However, recent studies have revealed that in 368 369 phenotype.63 Although the microenvironmental stimuli and tissues like the liver and spleen, the macrophages differentiate 370 from yolk sacederived embryonic precursors and locally selfthe phenotypes are diverse, macrophages have been primarily 371 renew during both steady state and infection.29 classified into two major phenotypes on the basis of the type 1 372 Table 1

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Tissue- and Organ-Specific Functions of Macrophages


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373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 helper T-cell (Th1)/type 2 helper T-cell (Th2) polarization, 392 according to the T-cell literature.10,39,58,64 The introduction of 393 the Th1/Th2 paradigm and the significance of the inflamma394 395 tory and cytotoxic nature of the macrophages produced the 396 concept that only cytokines secreted by Th1 cells, such as 397 IFN-g and tumor necrosis factor-a (TNF-a), enhanced 398 macrophage activation. These macrophages were then termed 399 proinflammatory, classically activated, or type I macrophages 400 (M1s). Conversely, Th2 cytokines, such as IL-4 and IL-10, 401 inhibited macrophage activation and were called anti402 inflammatory, alternatively activated, or type II macrophages 403 65,66 (Figure 2). Although M1 macrophages possess 404 ½F2 (M2s) potent microbicidal properties and support IL-12emediated 405 Th1 responses, which are essential in the early stages of tissue 406 407 repair, M2 macrophages support Th2-related effector functions 408 and play a more reparative role in the later stages of the repair 409 ½F3 process (Figure 3). 410 On the basis of the stimulus from the microenvironment, 411 M2 macrophages are further subdivided into three subtypes: 412 i) M2a is a profibrotic phenotype and is stimulated by IL-4 413 or IL-13,67 ii) M2b is induced by combined exposure to 414 immune complexes and Toll-like receptor or IL-1 receptor 415 agonists,68 and iii) M2c is stimulated by IL-10, transforming 416 growth factor (TGF)-b, or glucocorticoids and not only 417 causes suppression of inflammation but also promotes 418 419 neovascularization.67 The antimicrobial functions of M1 420 macrophages are linked to up-regulation of enzymes, such 421 as inducible nitric oxide synthase, that generates nitric oxide 422 from L-arginine.69 M2 subsets generally demonstrate an 423 IL-2low, IL-23low, and IL-10high phenotype combined with 424 high levels of scavenger, mannose, and galactose-type re425 ceptors. They repurpose arginine metabolism to ornithine 426 and polyamine, which promotes growth.70 Macrophages 427 play a major role in the transition from the inflammatory to 428 the proliferative phase, which decides the fate of the injury 429 site. By releasing a wide variety of growth factors and 430 431 cytokines, macrophages recruit other cell types, such as 432 fibroblasts, which, once activated, organize the new tissue 433 matrix and promote angiogenesis. Macrophages are also 434

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Figure 2 Macrophage polarization from a proinflammatory M1 to an anti-inflammatory M2 phenotype is mediated by a set of specific factors, including efferocytosis of apoptotic cells present at the site of inflammation, cytokines, lipid mediators, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and cell signaling mediators c-Jun N-terminal kinase (JNK), janus kinase (JAK)STAT, and phosphatidylinositol 3-kinase (PI3K). The miRNAs and long noncoding RNAs (lncRNAs) also support macrophage polarization. The expressions of specific genes are altered in transition from M1 to M2. Up-regulated genes are shown with red arrowheads, whereas down-regulated genes are shown with green arrowheads. Arg-1, arginine-1; iNOS, inducible nitric oxide synthase; LPS, lipopolysachharide; MHC-II, major histocompatibility complex class II; TNF-a, tumor necrosis factor a; Ym-1, chitinase 3-like 3.

known to modulate fibrosis and scarring during the reparative process of wound healing (Figure 3).71

Wound Macrophages The macrophages that infiltrate the wounds are often referred to as wound macrophages. Studies performed to characterize wound macrophage phenotypes in our and other laboratories suggest that macrophage polarization state at the repair site is highly dynamic and is dependent on the wound environment. Therefore, at a given time, a continuum of macrophage polarization states is expected at the wound site. Characterization of distinct circulating monocyte populations that infiltrated into an inflammatory site demonstrated that, although the phenotype of macrophages isolated from murine wounds reflected those of their precursor monocytes partially and changed with time, they did not correspond to the current macrophage classifications (ie, M1 or M2).72 Daley et al73 reported that wound macrophages share the characteristics of both classically and alternatively activated macrophages. The production of proinflammatory cytokines, such as TNF-a and IL-6, was more in day 1 wound macrophages, whereas day 7 wound macrophages produced more TGF-b.73 The study also reported that, unlike the regulatory macrophages, wound macrophages did not release IL-10.73 This observation of IL-10 is contentious because studies from our laboratory clearly demonstrated production of IL-10 by wound macrophages, with a significant increase in the levels at a late phase of healing versus an early phase of wound healing.74 Our laboratory provided first evidence on the gene expression profile of wound macrophages extracted from chronic human wounds.75 Genome-wide screening for transcripts that were differentially expressed in chronic wound macrophages compared with blood monocyteederived macrophages resulted in the identification of a focused set of 202 up-regulated and 49 down-regulated probe sets. These data suggest that wound macrophages have unique characteristics compared with cultured blood monocyteederived macrophages.75

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Figure 3

Macrophage plasticity in tissue repair. After injury, the macrophage (Mf) arrives at the site of injury from the systemic circulation via diapedesis. In the early phase, the inflammatory milieu drives macrophage toward M1 polarization. M1 macrophages possess potent microbicidal properties and support IL-12emediated type 1 helper T-cell responses, which are essential in the early stages of wound healing. In the late inflammatory phase, the change in wound microenvironment and the process of efferocytosis (clearance of apoptotic cells) drive the M1 macrophages toward M2 polarization. M2 supports type 2 helper T-cellerelated effector functions and plays a more reparative role in the later stages of wound healing. Macrophages play a major role in the transition of the wounds from the inflammatory to the resolution or proliferative phase, driving angiogenesis and matrix production. PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

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Macrophage Plasticity

The paradigm of wound macrophages is unique and led to an interesting model of in vivo macrophage activation, which was proposed by Mosser and Edwards.20 According to this classification, instead of phenotypic markers, macrophages are classified on the basis of functionsdhost defense, wound healing, and immune regulation.20 This method is helpful because instead of two groups of macrophages, this concept provides a continuum of macrophage population on the basis of their function. The approach of classification of Mosser and Edwards20 is helpful in accommodating the macrophages that share the phenotypes of both populations, such as in wound healing. Widespread use of multiple definitions of macrophage activation, including terms such as M1 and M2, alternative and classic activation, regulatory macrophages, and subdivisions originating from the parent terms is contentious and confusing.76 With the goal of unifying experimental standards for diverse experimental scenarios, a set of standards encompassing three principles has been proposed: i) the source of macrophages, ii) the definition of the activators, and iii) a consensus collection of markers to describe macrophage activation. Progress in this direction will help establish a common framework for macrophage activation nomenclature.76

Can Macrophages Switch Polarization State? It is contentious whether the reparative macrophages that are found predominantly during the healing phase originate from a subset of entirely newly recruited monocytes or are derived as a result of the M1 macrophages switching their phenotype.74 There are three major hypotheses attempting to explain the phenomenon13: Specific subsets of monocytes can assume a specific phenotype. For example, Ly6Cþ monocytes become M1 macrophages, and Ly6C monocytes become M2 macrophages. However, the observations


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that LY6C cells differentiate to M1 and LY6Cþ cells to Q9 M213 as well as differentiation of M1 to M224,77 weaken this argument. The second view proposes that monocytes are recruited as waves into a tissue during inflammatory response. Monocytes recruited into the tissue at different times come across different microenvironmental signals that can polarize them into specific phenotypes, depending on early versus late inflammatory phase. The observation that M2 macrophages derive largely from M1 macrophages24,77 does not support the second view as well. The third view suggests that, depending on environmental cues, macrophages can differentiate from an M1 to an M2 phenotype. Porcheray et al77 investigated whether the same macrophage population involved in inflammatory response switches to a more reparative phenotype in the later phase of healing. It was clearly demonstrated that the activation state of the macrophages was rapidly and fully reversible, suggesting that a given cell may participate sequentially in both the induction and the resolution of inflammation.77 Studies from our laboratory also support the third view. We have demonstrated that successful efferocytosis and molecular mediators, such as miR-21, switch macrophages to an antiinflammatory phenotype that helps in the resolution of inflammation.24,74 Such switching from a proinflammatory to an anti-inflammatory phenotype was facilitated by modifying intracellular noncoding miRNA miR-21 or miR21 target protein PTEN and PDCD4 levels.24 Earlier, we Q10 had demonstrated that under conditions of diabetes, a dysfunction in efferocytosis forces wound macrophages to remain in a proinflammatory (M1) phase.74 The conversion of proinflammatory M1 macrophages to anti-inflammatory M2 macrophages is beneficial in circumstances where resolution of inflammation is required, as in wound healing. However, in cancer, macrophages tend to harbor more of an anti-inflammatory M2 phenotype, where

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Das et al conversion to an M1 phenotype might aid in removal of cancer cells. Lipopolysaccharide (LPS) has been reported to induce an M1 phenotype from an M2 phenotype.78 Furthermore, in vitro studies have shown that CD40 activation with IFN-g was required to effectively reprogram tumor-induced M2-like macrophages into activated IL12eproducing M1 cells.79 Furthermore, reports have indicated that when fully polarized M2 macrophages present antigen to Th1 cells in a tumor milieu, this interaction results in repolarization of M2 to M1 macrophages.80

formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate, has been implicated in switching of macrophages from M1 to M2 phenotype.85 Macrophages lacking src homology 2econtaining inositol phosphatase exhibit elevated PI-3,4,5-P3 levels, which Q12 switch nitric oxideeproducing M1 macrophages to reparative M2 macrophages, suggesting that src homology 2econtaining inositol phosphatase suppresses the production of M2 macrophages.86

Cell Signaling Mediators Metabolic Reprogramming in Macrophage Plasticity An excellent review recently highlighted the significance of metabolic state in macrophage plasticity.70 A [1,2-(13)C(2)] glucose tracerebased metabolomics approach was adapted to characterize the metabolic flux distributions in macrophages stimulated through the M1 and M2 pathways. The data showed that activated macrophages are essentially glycolytic cells, and a clear cutoff between the M1 and the M2 pathway exists at the metabolic state level.81 In M1 macrophages on activation, aerobic glycolysis is induced, resulting in increased glucose uptake. Concomitantly, the induction of a pentose phosphate pathway occurs. The pentose phosphate pathway provides NADPH for the production of reactive oxygen species (ROS) and attenuation in mitochondrial respiratory change, resulting in augmented ROS production. M2 macrophages, on the other hand, use fatty acid oxidation. Forcing oxidative metabolism in an M1 macrophage potentiated the M2 phenotype.70 One of the mechanisms of differential metabolic states between M1 and M2 macrophages has been identified as a switch in the expression of phosphofructokinase 2 isoenzymes that appears to be a common event after LPS/IFN-g or Toll-like receptor 2, 3, 4, and 9 stimulation (M1 pathway).81 The differences in the metabolic states of M1 and M2 are well accepted. However, the underlying mechanisms involved in switching between metabolic states are not well understood.70

Mechanisms of Macrophage Polarization and Plasticity

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Macrophages respond to environmental cues (eg, microbial products, damaged cells, and activated lymphocytes) with the acquisition of distinct functional phenotypes. Macrophage plasticity is extended to other cell types too, because they have been shown to transdifferentiate to endothelial cells.82,83 Transcriptional regulation of macrophage polarization about transcription factors (STATs, IRFs, and peroxisome proliferator-activated receptor-g) in activation of M1 or M2 polarization has been comprehensively reviewed.84 This review, therefore, has been limited to discussion on novel mechanistic underpinning of polarization. Among other regulators, phospholipase C b2, responsible for catalyzing the

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The cAMP response element-binding protein is a crucial transcription factor for up-regulating IL-10 and arginine-1, which are associated with the M2 phenotype, and repressing M1 activation. Deletion of two cAMP response elementbinding protein binding sites from the C/EBPb gene promoter Q13 blocks the downstream induction of anti-inflammatory genes associated with M2-like macrophage activation. Muscular Q14 injury in mice carrying the mutated C/EBPb promoter efficiently clear injured muscle from necrotic debris, but display severe defects in muscle fiber regeneration. This confirms the persistence of inflammatory macrophages in damaged muscles of these mice.87 Interestingly, increased AMP protein kinase activity has been associated with a decreased proinflammatory status of macrophages.88 Indeed, AMP protein kinase a1/ macrophages fail to adopt an anti-inflammatory (M2) phenotype and display a defect in the phagocytic activity.89 In skeletal muscle wounds, mitogen-activated protein kinase phosphatase (MKP)-1 facilitates transition from M1 to M2 phenotype.90 Gene-expression analyses on MKP-1/ muscle macrophages indicate that MKP-1 controls the inflammatory response and the switch from early proinflammatory to late antiinflammatory macrophage phenotype via p38 mitogenactivated protein kinase down-regulation. Mice deficient in MKP-1 display defective muscle regeneration with persistence of damage and impaired growth of regenerating myofibers. The wild-type phenotype is restored by MKP-1þ/þ bone-marrow transplantation.90 A key molecule of signal transduction pathway Akt also contributes to macrophage polarization, depending on its isoform. Akt1 ablation in macrophages produces an M1 macrophage phenotype, and Akt2 ablation results in an M2 phenotype.91 Akt2/ mice are more resistant to LPS-induced endotoxin shock and to dextran sulfate sodiumeinduced colitis than wild-type mice, whereas Akt1 ablation renders the mice more sensitive to LPS-induced endotoxin shock.91 Furthermore, it has been shown that recepteur d’origine nantais (RON) receptor tyrosine kinase drives macrophage Q15 polarization to M2. RON knockout mice are sensitive to LPS challenge.92 RON signaling decreases proinflammatory cytokine production, suppresses nitric oxide synthase, and, at the same time, up-regulates arginase.93 The presence of macrophages at a wound site in the early phase of healing, characterized by low oxygen levels,94 suggests a role of hypoxia in macrophage phenotype and function.

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Macrophage Plasticity Indeed, the transcription factor hypoxia-inducible factor (HIF) plays a critical role in the adaptation of macrophages at the injury site.70 HIF1a has been associated with M1 macrophage activation, whereas HIF2a has been linked to an M2 phenotype. Such differential roles of HIF isoforms in macrophage polarization at the wound site are not clearly understood yet.70

miRNA and Long Noncoding RNAs

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miRNAs are short noncoding RNAs of approximately 21 to 23 nucleotides in length. The database of miRNAs, miRBase, enlists 30,424 mature miRNA sequences across different species (miRBase version 20). miRNAs are primarily involved in post-transcriptional silencing of genes. They bind to the target mRNA transcripts leading to translational repression or degradation of mRNA transcripts. This pairing between miRNA and mRNA is usually of partial complementarity, resulting in a single miRNA targeting numerous mRNA transcripts. A single miRNA, on average, is predicted to target approximately 200 mRNA transcripts.95 What makes this regulatory network even more interesting is the observation that a single mRNA is targeted by more than one miRNA, depending on the length of the 30 -untranslated region of the mRNA. Recent studies, including those in our laboratory, emphasize the role played by miRNAs in regulating macrophage plasticity. The miRNA let-7c promotes M2 macrophage polarization and suppresses M1 polarization.96 The let-7c down-regulates C/EBP-d, an important transcriptional factor that is required for a sustained Toll-like receptor 4einduced inflammatory response, which promotes the M1 phenotype.97 Similar to the role of let-7c, miR-124 diminishes M1 polarization and enhances M2 polarization in bone marrowederived macrophages from mice. Overexpression of miR-124 reduces expression of the surface markers CD45, CD11b, F4/80, major histocompatibility complex class II, and CD86, but increases the expression of the M2 phenotypic markers FIZZ1 and arginine1. In contrast, knockdown of miR-124 enhances the expression of the surface markers CD45 and major histocompatibility complex class II in bone marrowederived macrophages.98 C/EBP-a was identified as the mediator of the effect of miR-124 on macrophage polarization. Such as let-7c and miR-124, miR-223 promotes the M2 fate. miR-223 is upregulated in LPS-treated macrophages, but down-regulated in IL-4etreated bone marrowederived macrophages.99 miR-223edeficient macrophages were hypersensitive to LPS stimulation, whereas such macrophages exhibited delayed responses to IL-4 compared with controls.99 The polarization was mediated via Pknox1, a proinflammatory gene that was identified in these studies as a target of miR223. Our group has reported that miR-21 enables efficient resolution of inflammation in postefferocytosis macrophages. We speculate that such resolution of inflammation will drive macrophages toward the M2 phenotype via PTENeNF-kB and PDCD4-AP1 pathways.24


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Apart from small noncoding RNAs, long noncoding RNAs (lncRNAs) are also emerging as factors that might influence macrophage plasticity. Although direct evidence of lncRNAs in determining macrophage fate is lacking, their influence on the process cannot be ruled out on the basis of upcoming reports. lncRNA E330013P06 overexpression in macrophages induced proinflammatory genes and enhanced responses to inflammatory signals.100 Similarly, studies with linc1992 demonstrated that this lncRNA forms a heterogeneous nuclear ribonucleoprotein L that may regulate transcription of the TNF-a gene by binding to its promoter. Knockdown of linc1992 caused dysregulation of TNF-a Q19 during innate activation of THP1 macrophages.101

Lipid Mediators The role of lipid and lipoprotein molecules adds a novel element to the regulation of macrophage polarization. Oxidized lowdensity lipoprotein regulates the gene expression profile of M1 and M2 macrophages derived from cultured human monocytes.102 Molecular network analysis showed that most of the molecules in the oxidized low-density lipoproteineinduced M1 macrophages are directly or indirectly related to TGF-b1.102 Furthermore, it has been well documented that chemical mediators biosynthesized from arachidonic acid, which include prostaglandins and leukotriene B4, are involved in the activation of the initial phase of diapedesis.103,104 Lipid molecules derived from u-3 polyunsaturated fatty acid substrates play multiple roles, including stimulation of macrophage efferocytosis, IL-10 production, and resolution of inflammation. Resolvin E1, an eicosapentaenoic acid family member, promotes efferocytosis at concentrations as low as 1 nmol/L. In addition, the NADPH oxidase mediated ROS generation, and IL-10 production was induced.105 Maresin derived from docosahexaenoic acid acts as a switch from M1 to M2 transition.106

Macrophage Plasticity Transdifferentiation The major goal of tissue regeneration is to replace the injured tissue to near original. Transdifferentiation (ie, switch into another cell type) and reprogramming (ie, induction to become pluripotent cells) are critical processes of the regenerative process. Herein, we describe the significance of these processes in the context of macrophage plasticity. The ability of macrophages to transdifferentiate into endothelial cells, endothelial progenitor cells, or endothelial-like cells both in vitro and in vivo has been documented.107,108 The generation of endothelial progenitor cells from macrophages is crucial given the fact that this aspect of macrophage plasticity could be used to stimulate the revascularization of injured blood vessels in ischemic tissues. Macrophages have also been shown to infiltrate the corneal stroma and transdifferentiate into lymphatic endothelial cells.109 By overexpression of vascular endothelial

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growth factor, macrophages can be stimulated to transdifferentiate to the endothelial cell type.107 Pleiotrophin (PTN) expressed by macrophages under ischemic conditions can promote transdifferentiation of macrophages to endothelial cells both in vitro and in vivo. PTN-induced transdifferentiation appears to be regulated at the transcriptional level because both GATA-2 and GATA-3, transcription factors known to regulate the endothelial cell phenotype, are up-regulated by PTN in monocytic cells.110 Transdifferentiation of macrophage to other cell lineages, thus, cannot be ruled out, and reports in this direction will help us to understand macrophage plasticity more vividly.

Reprogramming Although studies related to functional plasticity of macrophages are still in early stages, work has been performed to alter macrophage fate in vivo at wanted sites. Discussed in the previous section, PTN can induce transdifferentiation of macrophage to endothelial cells. The authors demonstrated that under in vivo conditions in mice, PTN-expressing monocytic cells specifically incorporate into blood vessels.110 Tumorinfiltrating macrophages and TAMs have been described as suppressor macrophages that display anti-inflammatory and immunosuppressive activities.111,112 In vivo delivery of IL-12 to tumor sites results in the conversion of tumor-infiltrating macrophages and TAMs from the anti-inflammatory phenotype to the proinflammatory phenotype.113 IL-12etreated macrophages secrete IL-15, demonstrating their antiinflammatory nature. IL-12 treatment could alter the function of these tumor-associated suppressor macrophages. Analysis of tumor-infiltrating macrophages and distal TAMs revealed that IL-12, both in vivo and in vitro, induced a rapid reduction of tumor-supportive macrophage activities (IL-10, monocyte chemoattractant protein-1, migration inhibitory factor, and TGF-b production) and a concomitant increase in proinflammatory and proimmunogenic activities.113 Macrophages are traditionally known to be derived from myeloid cells. However, it has been recently shown that induced pluripotent cells (iPSCs) can also produce functional macrophages,114 as shown by the generation of human iPS cell clones by lentivirus-mediated transfer of Yamanaka factor (Oct3/4, Sox2, c-Myc, and Klf4) transgenes into dermal fibroblasts, followed by treatment with granulocyte-macrophage CSF, macrophage CSF, and IL-4. Although iPSC can produce macrophages, the functionality of the macrophage will be dependent on the source of iPSC. The evidence was provided by Jiang et al,115 who studied patients experiencing chronic granulomatous disease, an inherited disorder of macrophages in which NADPH oxidase is defective in generating ROS. Chronic granulomatous disease patientespecific iPSC-derived macrophages possessed normal phagocytic properties but were deficient in ROS production. This evidence also supported the notion that macrophages originating from iPSCs behave similar to those originating from myeloid cells.

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Perspectives Monocytes and macrophages are plastic cells whose functions are governed by local microenvironmental cues. Macrophages may assume multiple phenotypes, depending on conditions at the region of interest. Therefore, the polarization of macrophage should be considered as a continuum of diverse functional states, of which M1 and M2 activation states represent two extremes in the state of macrophage polarization. The local environment of a tissue repair site is highly dynamic and responsive to the progressive healing or futile nonhealing outcomes. Thus, at the site of tissue injury, macrophages may exist at any one point in the continuum of macrophage polarization states. In addition, monocytes may transdifferentiate to several cell types influencing the fate of tissue repair. Current evidence in this direction is scanty but lays the foundation to warrant further investigation. Given the versatility of monocytes and macrophages at the site of tissue injury, together with their profound influence on repair outcomes, it will be of substantial therapeutic value to gain traction on interventions aimed at tuning macrophage fate at the site of tissue injury.

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Macrophage plasticity in skeletal muscle repair.

miRNA control of tissue repair and regeneration.

Inflammation and metabolism in tissue repair and regeneration.

Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.

Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization.

Affinity-based drug delivery systems for tissue repair and regeneration.

Fibroblast growth factors as tissue repair and regeneration therapeutics.

The benefits of oxidative stress for tissue repair and regeneration.

Is monocyte- and macrophage-derived tissue transglutaminase involved in inflammatory processes?

Targeting Adult Mesenchymal Stem Cells Plasticity for Tissue Regeneration.

Islet cell plasticity and regeneration.

Repair and Regeneration.

Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis.

miR-24 Regulates Macrophage Polarization and Plasticity.

regeneration.

Modulation of tissue repair by regeneration enhancer elements.

The cellular and molecular mechanisms of tissue repair and regeneration as revealed by studies in Xenopus.

The monocyte-macrophage axis in the intestine.

Rethinking differentiation: stem cells, regeneration, and plasticity.

Purinergic and calcium signaling in macrophage function and plasticity.

Skin Regeneration, Repair, and Reconstruction.

Effect of prostaglandin I2 analogs on monocyte chemoattractant protein-1 in human monocyte and macrophage.

Macrophage Phenotype in Kidney Injury and Repair.

Telocytes in cardiac regeneration and repair.