Mechanisms regulating skin immunity and inflammation

Nature Reviews Immunology

Volumn 14, Issue 5, 2014, Pages 289-301

  Pasparakis, Manolis ^a   Haase, Ingo ^a   Nestle, Frank O ^b  

^a UNIVERSITY OF COLOGNE   (Germany)

^b BHF Centre for Regenerative Medicine and BHF Centre of Excellence and the Biomedical Research Centre at Guy s St Thomas NHS Foundation Trust and King s College London   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MARROW CELL; CELL DIFFERENTIATION; CELL TYPE; CHRONIC INFLAMMATION; COMMENSAL; DENDRITIC CELL; DERMATITIS; EPITHELIUM CELL; HOST RESISTANCE; HUMAN; IMMUNE RESPONSE; KERATINOCYTE; LANGERHANS CELL; LYMPHOID CELL; MACROPHAGE; MAST CELL; MONOCYTE; NONHUMAN; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; IMMUNITY; INFLAMMATION; SKIN; SKIN DISEASES;

EID: 84899630165     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3646     Document Type: Review

References (141)

1. Nestle, F. O., Di Meglio, P., Qin, J. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nature Rev. Immunol. 9, 679-691 (2009).
2. Di Meglio, P., Perera, G. K. & Nestle, F. O. The multitasking organ: recent insights into skin immune function. Immunity 35, 857-869 (2011).
3. Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265-273 (2006).
4. Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167-1181 (2012).
5. Greter, M. et al. Stroma-derived interleukin?34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050-1060 (2012).
6. Wang, Y. et al. IL?34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nature Immunol. 13, 753-760 (2012).
7. Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nature Immunol. 13, 744-752 (2012).
8. Tamoutounour, S. et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925-938 (2013).
9. Tussiwand, R. et al. Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 490, 502-507 (2012).
10. Schraml, B. U. et al. Genetic tracing via DNGR?1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, 843-858 (2013).
11. Igyarto, B. Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260-272 (2011).
12. Stoitzner, P. et al. Langerhans cells cross-present antigen derived from skin. Proc. Natl Acad. Sci. USA 103, 7783-7788 (2006).
13. Igyarto, B. Z. & Kaplan, D. H. Antigen presentation by Langerhans cells. Curr. Opin. Immunol. 25, 115-119 (2013).
14. Gao, Y. et al. Control of T helper 2 responses by transcription factor IRF4?dependent dendritic cells. Immunity 39, 722-732 (2013).
15. Kumamoto, Y. et al. CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39, 733-743 (2013).
16. Flutter, B. & Nestle, F. O. What on "irf" is this gene 4? Irf4 transcription-factor-dependent dendritic cells are required for T helper 2 cell responses in murine skin. Immunity 39, 625-627 (2013).
17. Abram, C. L., Roberge, G. L., Pao, L. I., Neel, B. G. & Lowell, C. A. Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38, 489-501 (2013).
18. Idoyaga, J. et al. Specialized role of migratory dendritic cells in peripheral tolerance induction. J. Clin. Invest. 123, 844-854 (2013).
19. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59-70 (2003).
20. Wohn, C. et al. Langerinneg conventional dendritic cells produce IL?23 to drive psoriatic plaque formation in mice. Proc. Natl Acad. Sci. USA 110, 10723-10728 (2013).
21. Lowes, M. A. et al. Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti?CD11a). Proc. Natl Acad. Sci. USA 102, 19057-19062 (2005).
22. Wang, C. Q. et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS ONE 6, e18907 (2011).
23. Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497-510 (2008).
24. Romano, E. et al. Human Langerhans cells use an IL?15R?α/IL?15/ pSTAT5?dependent mechanism to break T?cell tolerance against the self-differentiation tumor antigen WT1. Blood 119, 5182-5190 (2012).
25. Seneschal, J., Clark, R. A., Gehad, A., Baecher-Allan, C. M. & Kupper, T. S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873-884 (2012).
26. Gunther, C., Starke, J., Zimmermann, N. & Schakel, K. Human 6?sulfo LacNAc (slan) dendritic cells are a major population of dermal dendritic cells in steady state and inflammation. Clin. Exp. Dermatol. 37, 169-176 (2012).
27. Nestle, F. O., Zheng, X. G., Thompson, C. B., Turka, L. A. & Nickoloff, B. J. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J. Immunol. 151, 6535-6545 (1993).
28. Chu, C. C. et al. Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL?10 and induce regulatory T cells that suppress skin inflammation. J. Exp. Med. 209, 935-945 (2012).
29. Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60-73 (2012).
30. Chu, C. C., Di Meglio, P. & Nestle, F. O. Harnessing dendritic cells in inflammatory skin diseases. Semin. Immunol. 23, 28-41 (2011).
31. Wollenberg, A., Kraft, S., Hanau, D. & Bieber, T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J. Invest. Dermatol. 106, 446-453 (1996).
32. Gilliet, M., Cao, W. & Liu, Y. J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nature Rev. Immunol. 8, 594-606 (2008).
33. Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135-143 (2005).
34. Ronnblom, L. & Pascual, V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17, 394-399 (2008).
35. Guiducci, C. et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J. Exp. Med. 207, 2931-2942 (2010).
36. Flutter, B. & Nestle, F. O. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138-3146 (2013).
37. Sisirak, V. et al. CCR6/CCR10?mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Blood 118, 5130-5140 (2011).
38. Drobits, B. et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J. Clin. Invest. 122, 575-585 (2012).
39. Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284-1288 (2011).
40. Cain, D. W. et al. Identification of a tissue-specific, C/EBPβ-dependent pathway of differentiation for murine peritoneal macrophages. J. Immunol. 191, 4665-4675 (2013).
41. Von Stebut, E. Immunology of cutaneous leishmaniasis: the role of mast cells, phagocytes and dendritic cells for protective immunity. Eur. J. Dermatol. 17, 115-122 (2007).
42. Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, 599-610 (2013).
43. Zigmond, E. et al. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076-1090 (2012).
44. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958-969 (2008).
45. Fuentes-Duculan, J. et al. A subpopulation of CD163? positive macrophages is classically activated in psoriasis. J. Invest. Dermatol. 130, 2412-2422 (2010).
46. Sugaya, M. et al. Association of the numbers of CD163+ cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma. J. Dermatol. Sci. 68, 45-51 (2012).
47. Wang, H. et al. Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation. J. Clin. Invest. 116, 2105-2114 (2006).
48. Stratis, A. et al. Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation. J. Clin. Invest. 116, 2094-2104 (2006).
49. Meng, G., Zhang, F., Fuss, I., Kitani, A. & Strober, W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30, 860-874 (2009).
50. Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176-185 (2013).
51. Kataru, R. P. et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113, 5650-5659 (2009).
52. Egawa, M. et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin?4. Immunity 38, 570-580 (2013).
53. Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524-528 (2012).
54. St John, A. L. et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc. Natl Acad. Sci. USA 108, 9190-9195 (2011).
55. Nakamura, Y. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397-401 (2013).
56. Nakamura, Y. et al. Critical role for mast cells in interleukin?1β? driven skin inflammation associated with an activating mutation in the Nlrp3 protein. Immunity 37, 85-95 (2012).
57. Hershko, A. Y. et al. Mast cell interleukin?2 production contributes to suppression of chronic allergic dermatitis. Immunity 35, 562-571 (2011).
58. Streilein, J. W. Skin-associated lymphoid tissues (SALT): origins and functions. J. Invest. Dermatol. 80, 12s-16s (1983).
59. Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nature Rev. Immunol. 4, 211-222 (2004).
60. Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731-736 (2004).
61. Boyman, O., Conrad, C., Tonel, G., Gilliet, M. & Nestle, F. O. The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol. 28, 51-57 (2007).
62. Conrad, C. et al. α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nature Med. 13, 836-842 (2007).
63. Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431-4439 (2006).
64. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nature Immunol. 10, 524-530 (2009).
65. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553-564 (2010).
66. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216-219 (2011).
67. Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037-7042 (2012).
68. Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463-467 (2012).
69. Liu, L. et al. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nature Med. 16, 224-227 (2010).
70. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227-231 (2012).
71. Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510-5514 (2011).
72. Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl Med. 4, 117ra7 (2012).
73. Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538-542 (2011).
74. Vantourout, P. & Hayday, A. Six?of?the-best: unique contributions of γδ T cells to immunology. Nature Rev. Immunol. 13, 88-100 (2013).
75. Barbee, S. D. et al. Skint?1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl Acad. Sci. USA 108, 3330-3335 (2011).
76. Silva-Santos, B. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL?17?producing γδ T cells. Eur. J. Immunol. 40, 1873-1876 (2010).
77. Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505-518 (2011).
78. Gray, E. E., Suzuki, K. & Cyster, J. G. Cutting edge: identification of a motile IL?17?producing γδ T cell population in the dermis. J. Immunol. 186, 6091-6095 (2011).
79. Becher, B. & Pantelyushin, S. Hiding under the skin: interleukin?17?producing γδ T cells go under the skin? Nature Med. 18, 1748-1750 (2012).
80. Cai, Y. et al. Pivotal role of dermal IL?17?producing γδ T cells in skin inflammation. Immunity 35, 596-610 (2011).
81. Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252-2256 (2012).
82. Gray, E. E. et al. Deficiency in IL?17?committed Vγ4+ γδ T cells in a spontaneous Sox13?mutant CD45.1+ congenic mouse substrain provides protection from dermatitis. Nature Immunol. 14, 584-592 (2013).
83. Van Belle, A. B. et al. IL?22 is required for imiquimodinduced psoriasiform skin inflammation in mice. J. Immunol. 188, 462-469 (2012).
84. Bouchaud, G. et al. Epidermal IL?15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man. J. Exp. Med. 210, 2105-2117 (2013).
85. Mabuchi, T. et al. CCR6 is required for epidermal trafficking of γδ?T cells in an IL?23?induced model of psoriasiform dermatitis. J. Invest. Dermatol. 133, 164-171 (2013).
86. Tortola, L. et al. Psoriasiform dermatitis is driven by IL?36?mediated DC?keratinocyte crosstalk. J. Clin. Invest. 122, 3965-3976 (2012).
87. Gatzka, M. et al. Reduction of CD18 promotes expansion of inflammatory γδ T cells collaborating with CD4+ T cells in chronic murine psoriasiform dermatitis. J. Immunol. 191, 5477-5488 (2013).
88. Laggner, U. et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J. Immunol. 187, 2783-2793 (2011).
89. Witherden, D. A. & Havran, W. L. Crosstalk between intraepithelial γδ T cells and epithelial cells. J. Leukocyte Biol. 94, 69-76 (2013).
90. Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37, 314-325 (2012).
91. Gay, D. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nature Med. 19, 916-923 (2013).
92. Spits, H. et al. Innate lymphoid cells -a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145-149 (2013).
93. Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984-991 (2014).
94. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunol. 14, 564-573 (2013).
95. Kim, B. S. et al. TSLP elicits IL?33?independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl Med. 5, 170ra16 (2013).
96. Salimi, M. et al. A role for IL?25 and IL?33?driven type?2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939-2950 (2013).
97. Lizzul, P. F. et al. Differential expression of phosphorylated NF-κB/RelA in normal and psoriatic epidermis and downregulation of NF-κB in response to treatment with etanercept. J. Invest. Dermatol. 124, 1275-1283 (2005).
98. Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43-49 (2005).
99. Takahashi, H. et al. Extracellular regulated kinase and c?Jun N?terminal kinase are activated in psoriatic involved epidermis. J. Dermatol. Sci. 30, 94-99 (2002).
100. Zenz, R. et al. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res. Ther. 10, 201 (2008).
101. Zenz, R. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369-375 (2005).
102. Guinea-Viniegra, J. et al. TNF-α shedding and epidermal inflammation are controlled by Jun proteins. Genes Dev. 23, 2663-2674 (2009).
103. Chiang, M. F. et al. Inducible deletion of the Blimp?1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice. Proc. Natl Acad. Sci. USA 110, 6476-6481 (2013).
104. Briso, E. M. et al. Inflammation-mediated skin tumorigenesis induced by epidermal c?Fos. Genes Dev. 27, 1959-1973 (2013).
105. Uto-Konomi, A. et al. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin?20 receptor-related cytokines. PLoS ONE 7, e40343 (2012).
106. Reich, K. et al. Infliximab induction and maintenance therapy for moderate-to?severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366, 1367-1374 (2005).
107. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861-866 (2002).
108. Lind, M. H. et al. Tumor necrosis factor receptor 1?mediated signaling is required for skin cancer development induced by NF-κB inhibition. Proc. Natl Acad. Sci. USA 101, 4972-4977 (2004).
109. Kumari, S. et al. Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin?24?dependent psoriasis-like skin inflammation in mice. Immunity 39, 899-911 (2013).
110. Bonnet, M. C. et al. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572-582 (2011).
111. He, S. et al. Receptor interacting protein kinase?3 determines cellular necrotic response to TNF-α. Cell 137, 1100-1111 (2009).
112. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1?RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112-1123 (2009).
113. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332-336 (2009).
114. Weinlich, R. et al. Protective roles for caspase?8 and cFLIP in adult homeostasis. Cell Rep. 5, 340-348 (2013).
115. Panayotova-Dimitrova, D. et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 5, 397-408 (2013).
116. Nenci, A. et al. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Hum. Mol. Genet. 15, 531-542 (2006).
117. Omori, E. et al. TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J. Biol. Chem. 281, 19610-19617 (2006).
118. Omori, E., Morioka, S., Matsumoto, K. & Ninomiya-Tsuji, J. TAK1 regulates reactive oxygen species and cell death in keratinocytes, which is essential for skin integrity. J. Biol. Chem. 283, 26161-26168 (2008).
119. Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591-596 (2011).
120. Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637-641 (2011).
121. Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633-636 (2011).
122. Kajino-Sakamoto, R. et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143-1152 (2008).
123. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561 (2007).
124. Welz, P. S. et al. FADD prevents RIP3?mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334 (2011).
125. Wittkopf, N. et al. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase?8. Gastroenterology 145, 1369-1379 (2013).
126. Piao, X. et al. c?FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci. Signal. 5, ra93 (2012).
127. Krachler, A. M., Woolery, A. R. & Orth, K. Manipulation of kinase signaling by bacterial pathogens. J. Cell Biol. 195, 1083-1092 (2011).
128. Gilmore, T. D. & Herscovitch, M. Inhibitors of NF-κB signaling: 785 and counting. Oncogene 25, 6887-6899 (2006).
129. Mocarski, E. S., Upton, J. W. & Kaiser, W. J. Viral infection and the evolution of caspase 8?regulated apoptotic and necrotic death pathways. Nature Rev. Immunol. 12, 79-88 (2012).
130. Li, S. et al. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 501, 242-246 (2013).
131. Pearson, J. S. et al. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature 501, 247-251 (2013).
132. Findley, K. et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367-370 (2013).
133. Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190-1192 (2009).
134. Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nature Rev. Immunol. 12, 503-516 (2012).
135. Scholz, F., Badgley, B. D., Sadowsky, M. J. & Kaplan, D. H. Immune mediated shaping of microflora community composition depends on barrier site. PLoS ONE 9, e84019 (2014).
136. Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115-1119 (2012).
137. Rudikoff, D. & Lebwohl, M. Atopic dermatitis. Lancet 351, 1715-1721 (1998).
138. Myles, I. A. et al. Signaling via the IL?20 receptor inhibits cutaneous production of IL?1β and IL?17A to promote infection with methicillin-resistant Staphylococcus aureus. Nature Immunol. 14, 804-811 (2013).
139. Miller, L. S. et al. MyD88 mediates neutrophil recruitment initiated by IL?1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24, 79-91 (2006).
140. Cho, J. S. et al. IL?17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762-1773 (2010).
141. Perera, G. K. et al. Integrative biology approach identifies cytokine targeting strategies for psoriasis. Sci. Transl Med. 6, 223ra22 (2014).