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ScienceDirect Homeostatic inflammation in innate immunity Kensuke Miyake1,2 and Tsuneyasu Kaisho3,4,5 Innate immune sensors respond not only to microbial products but also to endogenous metabolites such as nucleic acids (NAs) and lipids. Toll-like receptors (TLRs) deliver a signal from the plasma membrane and also from endolysosomes, where NAs and lipids are catabolized. Interaction of TLRs with metabolites in endolysosomes leads to homeostatic TLR activation. Dendritic cells expressing NA-sensing TLRs are steadily activated by metabolites derived from the host or commensals and produce type I IFNs, thereby provoking various types of inflammatory conditions. Here, we discuss how homeostatic inflammation is induced by innate immune sensors and is involved in maintaining immune homeostasis and causing non-infectious inflammatory diseases. Addresses 1 Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 2 Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan 3 Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 4 Laboratory for Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan 5 Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama 641-8509, Japan Corresponding authors: Miyake, Kensuke ([email protected]) and Kaisho, Tsuneyasu ([email protected])

Current Opinion in Cell Biology 2014, 30:85–90 This review comes from a themed issue on Effects of endogenous immune stimulants Edited by Eicke Latz and Kensuke Miyake

http://dx.doi.org/10.1016/j.coi.2014.08.003 0952-7915/# 2014 Elsevier Ltd. All rights reserved.

Introduction Self-pathogen discrimination continues to be the most important issue in immunology. The innate immune system is thought to have been evolutionally optimized to sense a group of pathogens, but not to react against self. Despite the optimization, Toll-like receptors (TLRs), the founding family of pathogen sensors, still react with selfwww.sciencedirect.com

derived products such as fatty acids, phospholipids, and nucleic acids (NAs), and have been implicated in a variety of autoimmune and non-infectious inflammatory diseases [1]. Receptors in the immune system including B cell receptors, T cell receptors, and NK receptors, all signal from the cell surface, and their signaling is terminated by their internalization. Meanwhile, certain Toll-like receptors (TLRs) are unique in this regard; the endotoxin sensor, TLR4/MD-2, and NA-sensing TLRs such as TLR3/7/8/9 are capable of signaling in the endolysosomes [2], where endogenous TLR ligands like fatty acids, phospholipids, and NAs are present as metabolites (Figure 1). Microbial sensing in the endolysosomes, therefore, takes the risk of reacting with self-derived products that are not yet ‘a danger signal’, but still metabolites. Homeostatic TLR activation by endogenous metabolites may occur in the healthy state and even has a role in maintaining the integrity of the immune system. For example, antibody (Ab) production and T cell differentiation in the unperturbed state are altered by the lack of TLR signaling [3,4]. Notably, evidence is accumulating that certain metabolic diseases are influenced by a vicious circle driven by the interaction of pathogen sensors with endogenous metabolites. Pathologic inflammation in noninfectious inflammatory diseases can be understood as an outcome of uncontrolled homeostatic TLR activation. This article focuses on the interaction of TLRs with metabolites in dendritic cells (DCs) and macrophages at the steady and disease state and on the roles of DCs and macrophages in immune homeostasis.

Toll-like receptors respond to self-derived products Toll-like receptors (TLRs) sense a variety of microbial products. Cell surface TLRs including TLR4/MD-2, TLR1/TLR2, TLR6/TLR2 recognize microbial membrane lipids, whereas TLR3, TLR7, TLR8, and TLR9 are localized to intracellular organelles and recognize microbial NAs [5–7]. MD-2 has a hydrophobic pocket that accommodates acyl chains of lipopolysaccharides [8]. However, the hydrophobic pocket of MD-2 can also accommodate fatty acids and saturated and unsaturated fatty acids are known to activate or inhibit TLR4/MD-2 signaling, respectively [9]. Of note, TLR4/MD-2 responses to fatty acids can drive chronic inflammation in fat tissue during obesity [10]. The end product of lipid oxidation, v-(2-carboxyethyl) pyrrole (CEP), which is generated during inflammation and wound healing, can trigger TLR2 promoting angiogenesis [11]. Lipids are metabolized not only in cytoplasm but also in lysosomes Current Opinion in Immunology 2014, 30:85–90

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Figure 1

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Endolysosome as a platform for innate immune and metabolic sensors. The endotoxin sensors, TLR4/MD2, and NA-sensing TLRs such as TLR3/7/8/9 are located in the endolysosome and trigger the signaling pathway leading to the production of type I IFNs. In the endolysosome not only many metabolites, which include the endogenous innate immune sensor ligands, but also metabolic sensors, such as mTOR, are present. Innate immune and metabolic sensor systems are intimately integrated together, which is exemplified by the finding that mTOR is crucially involved in TLR7/9-induced IRF-7 activation and type I IFN production as well as in TLR4/MD-2-induced IFN-b production. The cytoplasmic DNA sensors and the downstream signaling adaptor STING are also activated by accumulated DNAs to induce type I IFNs, although it remains unclear how those sensors crosstalk with the endolysosomal sensor systems. DNases negatively regulate activation of the STING pathway.

where they are transported through endocytosis or autophagic pathways [12]. The TLR4/MD-2 complex is furthermore able to activate type I IFN-inducing signal in endolysosomes [13,14]. TLR7 and TLR8 respond not only to single stranded RNA but also to nucleoside analogues such as imiquimod. It is possible that TLR7 and TLR8 respond to a physiological metabolite generated during RNA digestion. TLR3 can also respond to self-derived RNAs. Upon ultraviolet B (UVB) exposure noncoding self RNA is released from damaged keratinocytes and induces proinflammatory cytokines in a TLR3-dependent manner [15]. In septic peritonitis and ischemic gut injury necrotic cells release NAs which are sensed by TLR3 and Current Opinion in Immunology 2014, 30:85–90

causing an inflammatory status [16]. Furthermore, TLR3 is also involved in the pathogenesis of a gastrointestinal syndrome caused by high-dose ionizing radiation [17]. Radiation induces cell damage and leakage of cellular RNA, which causes extensive cell death via TLR3 engagement. Thus, TLR3 is involved in the pathogenesis of several inflammatory responses by sensing self-derived NAs (Figure 2). Additionally, cytoplasmic DNA sensors are activated by self-derived DNA as described below.

Innate immune sensing by TLRs in endolysosomes Type I interferon (IFN) is induced in endolysosomes by TLR4/MD-2 or TLR3/7/8/9 [13,18]. Considering the interaction between metabolites and TLRs in the www.sciencedirect.com

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Figure 2

Psoriasis

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Roles of NA-sensing TLRs in various types of non-infectious inflammatory conditions. Upon tissue damage NAs are released from dead cells and stabilized by NA-binding substances, such as anti-NA Abs or anti-microbial peptides. Then NAs accumulate and are incorporated by DCs and activate DCs through NA-sensing sensors to produce type I IFNs, thereby causing various types of non-infectious inflammatory conditions. Certain types of commensal bacteria can induce TLR3-mediated and type I IFN-mediated immune protection through their RNAs. TLR7 and TLR9 function mainly in pDC. Meanwhile, TLR3 should function in CD103+CD11b DCs, which express TLR3 abundantly, although the responsible cells for TLR3-induced responses mostly remain unclear.

endolysosomes, it is important to understand the relationship between TLR-dependent IFN induction and metabolism in endolysosomes (Figure 1). The metabolic state of cells is determined by metabolic sensors including mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). mTOR is recruited to lysosomes and activated by lysosomal nutrients. mTOR is required for TLR7-dependent or TLR9dependent IFN-a production in pDCs by recruiting a downstream signaling adaptor MyD88 and by indirectly facilitating translation of interferon regulatory factor 7 (IRF7), a key transcription factor for type I IFN [19,20]. mTOR is also required for IFN-b induction by TLR4/ MD-2 in macrophages [21]. mTOR promotes protein translation, glycolysis, pyrimidine synthesis, and lipid biosynthesis while inhibiting autophagy [22]. Considering that TLR-activated cell responses lead to consumption of energy and metabolites such as amino acids and NAs, mTOR activation by TLRs likely functions to prepare the metabolic status of the responding cells for innate immune activation. Lysosomal digestion of lipids, proteins and NAs generates metabolites such as amino www.sciencedirect.com

acids, fatty acids, and nucleosides. Digestion of NAs negatively regulates NA-sensors, whereas the end product of lipid oxidation, v-(2-carboxyethyl) pyrrole (CEP), directly activates TLR2. Moreover, amino acids, the end products of protein digestion, activate mTOR, which is required for type I IFN induction by NA-sensing TLRs in lysosomes. These previous studies show a link among TLR activation, mTOR activation, and metabolism in endolysosomes.

Nucleic acids (NAs) digestion and innate immune responses Digestion of metabolites negatively regulates innate immune sensors. An inhibitory role of DNA digestion in NA sensors is shown by the studies on neutral DNase I in the circulation, acidic DNase II in lysosomes, and cytoplasmic DNase III. The loss of function mutation in the DNase I gene predisposes to systemic lupus erythematosis (SLE) in humans and mice [23,24]. Dnase1/ mice show SLE-like diseases with anti-nuclear Ab production which leads to the deposition of immune complexes in glomeruli and full-blown glomerulonephritis [24]. Dnase2a/ mice Current Opinion in Immunology 2014, 30:85–90

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show embryonic lethality due to anemia caused by constitutive production of IFN-b. Dnase2a/ Ifnar/ double mutant mice do not have anemia and are born healthy. However, DNA still accumulates in the lysosomes leading to chronic polyarthritis due to constitutive production of TNF-a [25]. Embryonic death and chronic polyarthritis are mediated by activation of Stimulator of type I IFN gene (STING), the signaling adaptor for cytoplasmic DNA sensors. Mutations in the gene of DNase III, also known as the 30 repair exonuclease 1 (Trex1) also cause activation of STING signaling, leading to type I IFN-dependent systemic inflammation [26] (Figure 2). It is not clear which cytoplasmic DNA sensors are activated in Dnase1/ mice, and why STING signaling leads to different pathologies in Dnase2a/ and Trex1/ mice. These findings indicate that the diseases are caused not merely by defective digestion of NAs and suggest that DNases are functionally linked with DNA sensors. Further studies need to focus on a link between NA digestion and NA-sensing.

Dysregulated NA digestion in the disease state Excessive stabilization of NAs in the host also leads to activation of NA sensing TLRs, including TLR3, TLR7 and TLR9, which can respond to endogenous NAs. AntiNA Abs, cationic antimicrobial peptides, or nuclear proteins bind to and stabilize NAs (Figure 1). As a consequence, the accumulated NAs activate TLR7 or TLR9 causing autoimmune diseases such as SLE or psoriasis. One dendritic cell subset, plasmacytoid dendritic cells (pDCs), expresses TLR7 and TLR9 and is featured by the ability to produce a large amount of type I IFNs in response to TLR7/9 signaling. These characteristics of PDCs play major roles in pathogenesis of several autoimmune diseases. Notably, while TLR7 and TLR9 signaling pathways are quite similar, they play differential roles in pathogenesis of autoimmunity. Several studies on TLR7-deficient or TLR9-deficient mice show that TLR7 and TLR9 are involved in progression and resolution of disease manifestations, respectively. It should be noted that one mutation (D34A) of UNC93B1, which functions as a chaperone for TLR7 and TLR9, leads to enhanced TLR7-signaling and impaired TLR9-signaling [27]. This imbalance is caused by the disturbance of the intracellular localization of TLR7 and TLR9. Mice harboring D34A mutation in UNC93B1 shows progressive systemic inflammation [28], indicating that the balance between TLR7 and TLR9 signaling is crucial for maintaining the immune homeostasis. Overload of NAs due to massive cell death is an important cause of dysregulated NA digestion. Intracellular nuclear proteins and/or metabolites including NAs are released and considered to be important inflammatory mediators. Caspase activation, which is induced by various metabolites, is crucially involved in this vicious cycle causing inflammation. Mice lacking a transcriptional regulator, Current Opinion in Immunology 2014, 30:85–90

IkB-z, develop lymphocyte-infiltrated dacryoadenitis accompanied with autoantibody production similar to what can be observed in a human autoimmune disease, Sjo¨gren syndrome [29]. This inflammation is prevented by caspase inhibitors and shown to be dependent on massive apoptosis of epithelial cells in the lacrimal grands. This model is suggestive of an involvement of caspase-mediated apoptosis in the pathogenesis of autoinflammatory diseases. However, it remains unclear whether or how cellular metabolites released from the epithelial cells are involved in the inflammation.

Homeostatic roles of dendritic cells Innate immune sensors function mainly in dendritic cells (DCs) or macrophages, which are called as Antigen (Ag) presenting cells. DCs activated by innate sensors are involved in various immune responses not only in microbial infections but also in noninfectious, sterile diseases. Analyses on DC-ablated mice also showed the crucial roles of DCs in maintaining immune homeostasis [30]. It should be noted that DCs are quite heterogeneous and consist of several subsets with subset-specific functions. PDCs are reported to produce type I IFN constitutively [31]. Constitutive type I IFN production primes PDCs for maximal TLR responses. TLR7 and TLR9 in PDCs also become activated in skin wounds since they respond to NAs released from dead cells [32]. Type I IFN produced from PDCs induces inflammatory responses to tissue damage and promotes re-epithelization of the injured skin. Conventional DCs (CDCs) are also divided into several subsets. One CDC subset, CD103+CD11b DC, is characterized by the ability to incorporate dead cells and to crosspresent soluble or cell-associated Ags for supporting generation of CD8+ cytotoxic T cells [33–35]. Furthermore, the DC subset can produce higher amounts of proinflammatory cytokines in response to various TLR ligands, such as LPS or CpG DNA, than the other DC subsets. These activities contribute to protective immunity that develops against viral infection or cancers. TLR3 expression is exclusively detected in CD103+CD11b DCs among the DC subsets and CD103+CD11b DCs is a main candidate DC subset involved in TLR3-mediated inflammatory responses that were described above. TLR3 is also involved in anti-inflammatory responses, as was found in the intestinal immune system. Strictly speaking, commensal bacteria are non-self in origin, but since the host coexists with commensal bacteria they can almost be regarded as self components. TLR3 detects dsRNA from one major commensal species, lactic acid bacteria and induces IFN-b in the intestine [36] (Figure 2). Through this induction, TLR3 can function as a sensor for commensal bacteria and contributes to anti-inflammatory immune responses. Although it remains unclear at present, TLR3 likely functions in the intestinal CD103+CD11b DC. The levels of NAs recognition by TLR3 should be regulated by multiple www.sciencedirect.com

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factors both from the host and from the commensal bacteria. It is also important to clarify how the TLR3 ligand NAs are generated or degraded in vivo.

Conclusion Considering that innate immune sensors can be activated by endogenous substances and that those substances are mainly metabolites, the control of their levels is crucial for maintaining immune homeostasis. Food is taken up orally and nutrients are absorbed in the intestine. The metabolites are generated from the ingested ingredients and processed by various tissues including metabolic organs such as liver and heart as well as by lymphoid organs. Surplus metabolites are excreted or reabsorbed in the kidney. Metabolite levels are determined by combinatory interactions within these processes. In addition to cardiocytes or hepatocytes, the metabolic status of innate and adaptive immune cells has recently been investigated and shown to play a major role for maintenance of immune homeostasis [37,38,39]. These studies are shedding light on the importance of the crosstalk between metabolic network and immune signaling pathways. Understanding the molecular basis for the crosstalk should greatly contribute to the elucidation of the immune homeostasis and should uncover possible therapeutic options to counteract immune dysregulation.

Acknowledgements The authors thank Prof. Tatsushi Muta, who unexpectedly and suddenly died of lung embolism in September 2013, for his contribution to the concept ‘homeostatic inflammation’ and for his dedication, as one of the founding members, to the program grant ‘Shizen Enshow’.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Marshak-Rothstein A, Rifkin IR: Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol 2007, 25:419-441.

2.

Barton GM, Kagan JC: A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 2009, 9:535-542.

3.

Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D: Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 2006, 314:1936-1938.

4.

Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R: Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2001, 2:947-950.

5.

Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K: Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol 2006, 24:353-389.

8.

Ohto U, Fukase K, Miyake K, Satow Y: Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 2007, 316:1632-1634.

9.

Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH: Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 2009, 284:27384-27392.

10. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S et al.: Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 2007, 27:84-91. 11. West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV: Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 2010, 467:972-976. 12. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ et al.: TFEB controls cellular lipid metabolism through a starvationinduced autoregulatory loop. Nat Cell Biol 2013, 15:647-658. 13. Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, Miyake K: Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun 2008, 368:94-99. 14. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R: TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 2008, 9:361-368. 15. Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, Martinez L, Greidinger EL, Yu BD, Gallo RL:  Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med 2012. Demonstrate that self RNAs are involved in various inflammatory responses through an NA sensor, TLR3. 16. Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL: TLR3 is an endogenous  sensor of tissue necrosis during acute inflammatory events. J Exp Med 2008, 205:2609-2621. See annotation to Ref. [15]. 17. Takemura N, Kawasaki T, Kunisawa J, Sato S, Lamichhane A, Kobiyama K, Aoshi T, Ito J, Mizuguchi K, Karuppuchamy T et al.:  Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat Commun 2014, 5:3492. See annotation to Ref. [15]. 18. Sasai M, Linehan MM, Iwasaki A: Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 2010, 329:1530-1534. 19. Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, Pulendran B: Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 2008, 9:1157-1164. 20. Colina R, Costa-Mattioli M, Dowling RJ, Jaramillo M, Tai LH, Breitbach CJ, Martineau Y, Larsson O, Rong L, Svitkin YV et al.: Translational control of the innate immune response through IRF-7. Nature 2008, 452:323-328. 21. Weinstein SL, Finn AJ, Dave´ SH, Meng F, Lowell CA, Sanghera JS, DeFranco AL: Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta. J Leuk Biol 2000, 67:405-414. 22. Efeyan A, Zoncu R, Sabatini DM: Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 2012, 18:524-533.

6.

Kaisho T, Akira S: Toll-like receptor function and signaling. J Allergy Clin Immunol 2006, 117(979-987) quiz 988.

23. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, Kuroda Y: Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001, 28:313-314.

7.

Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11:373-384.

24. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T: Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000, 25:177-181.

www.sciencedirect.com

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90 Effects of endogenous immune stimulants

25. Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S: Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 2006, 443:998-1002.

32. Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A, Arai N, Gallo RL, Digiovanni J, Gilliet M: Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med 2010, 207:2921-2930.

26. Gall A, Treuting P, Elkon KB, Loo YM, Gale M, Barber GN, Stetson DB: Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 2012, 36:120-131.

33. Shortman K, Heath WR: The CD8+ dendritic cell subset. Immunol Rev 2010, 234:18-31.

27. Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, Beutler B, Miyake K: Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. J Exp Med 2009, 206:1339-1350. 28. Fukui R, Saitoh S, Kanno A, Onji M, Shibata T, Ito A, Matsumoto M, Akira S, Yoshida N, Miyake K: Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 2011, 35:69-81. 29. Okuma A, Hoshino K, Ohba T, Fukushi S, Aiba S, Akira S, Ono M,  Kaisho T, Muta T: Enhanced apoptosis by disruption of the STAT3-IkB-z signaling pathway in epithelial cells induces Sjo¨gren’s syndrome-like autoimmune disease. Immunity 2013, 38:450-460. Shows that Sjo¨gren’s syndrome-like autoimmune diseases can be provoked by massive apoptosis of epithelial cells caused by disruption of STAT3-mediated IkB-z induction. 30. Bar-On L, Jung S: Defining dendritic cells by conditional and constitutive cell ablation. Immunol Rev 2010, 234:76-89. 31. Kim S, Kaiser V, Beier E, Bechheim M, Guenthner-Biller M, Ablasser A, Berger M, Endres S, Hartmann G, Hornung V: Selfpriming determines high type I IFN production by plasmacytoid dendritic cells. Eur J Immunol 2014, 44:807-818.

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34. Murphy KM: Transcriptional control of dendritic cell development. Adv Immunol 2013, 120:239-267. 35. Yamazaki C, Sugiyama M, Ohta T, Hemmi H, Hamada E, Sasaki I, Fukuda Y, Yano T, Nobuoka M, Hirashima T et al.: Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J Immunol 2013, 190:6071-6082. 36. Kawashima T, Kosaka A, Yan H, Guo Z, Uchiyama R, Fukui R, Kaneko D, Kumagai Y, You DJ, Carreras J et al.: Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-b. Immunity 2013, 38:1187-1197. 37. Pearce EL, Poffenberger MC, Chang CH, Jones RG: Fueling immunity: insights into metabolism and lymphocyte function. Science 2013, 342:1242454. 38. Maciolek JA, Alex Pasternak J, Wilson HL: Metabolism of activated T lymphocytes. Curr Opin Immunol 2014, 27C:60-74. 39. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY,  Redmann V, Freitas TC, Blagih J, van der Windt GJ et al.: TLRdriven early glycolytic reprogramming via the kinases TBK1IKKe supports the anabolic demands of dendritic cell activation. Nat Immunol 2014, 15:323-332. Clarifies the molecular mechanisms for metabolic changes leading to functional activation of DCs.

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Homeostatic inflammation in innate immunity.

Innate immune sensors respond not only to microbial products but also to endogenous metabolites such as nucleic acids (NAs) and lipids. Toll-like rece...
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