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Complement Modulates the Cutaneous Microbiome and Inflammatory Milieu

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Complement Modulates the Cutaneous Microbiome and Inflammatory Milieu Complement modulates the cutaneous microbiome and inflammatory milieu Christel Chehouda, Stavros Rafailb, Amanda S. Tyldsleya, John T. Seykoraa, John D. Lambrisb,1, and Elizabeth A. Gricea,1 Departments of aDermatology and bPathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 Edited by Andrea J. Tenner, University of California, Irvine, CA, and accepted by the Editorial Board August 2, 2013 (received for review April 26, 2013) The skin is colonized by a plethora of microbes that include systemic lupus erythematosus, lichen planus, xeroderma pigmento- commensals and potential pathogens, but it is currently un- sum, and recurrent cutaneous infection (15–18). known how cutaneous host immune mechanisms influence the Complement is triggered by one of three pathways (classical, composition, diversity, and quantity of the skin microbiota. alternative, or lectin), which all converge in the activation of the Here we reveal an interactive role for complement in cutaneous third complement component (C3). Following activation, the host–microbiome interactions. Inhibiting signaling of the com- release of biologically active proteins promote diverse defense plement component C5a receptor (C5aR) altered the composi- mechanisms such as microbial opsonization and phagocytosis, tion and diversity of the skin microbiota as revealed by deep direct lysis of target microbial cells through the membrane attack sequencing of the bacterial 16S rRNA gene. In parallel, we dem- complex (MAC), and the generation of effector molecules that fl onstrate that C5aR inhibition results in down-regulation of mediate recruitment and activation of in ammatory cells (13). genes encoding cutaneous antimicrobial peptides, pattern recog- This latter function, mediated by the complement C3a and C5a nition receptors, and proinflammatory mediators. Immunohisto- fragments, has been implicated in the modulation of innate and chemistry of inflammatory cell infiltrates in the skin showed acquired immune responses via cross-talk between the C5a re- reduced numbers of macrophages and lymphocytes with C5aR ceptor (C5aR) and pattern recognition receptor signaling (19). In this study, we focused on complement component C5a, the inhibition. Further, comparing cutaneous gene expression in most potent anaphylatoxin produced during complement acti- germ-free mice vs. conventionally raised mice suggests that the vation, and its role in cutaneous host–microbiome interactions of commensal microbiota regulates expression of complement genes fi fi mice maintained under speci c pathogen-free conditions. Sig- in the skin. These ndings demonstrate a component of host immu- naling of C5a through its receptor triggers proinflammatory and nity that impacts colonization of the skin by the commensal micro- – immunoregulatory actions, including enhanced leukocyte che- biota and vice versa, a critical step toward understanding host motaxis, neutrophil–endothelial cell adhesion, vascular perme- microbe immune mutualism of the skin and its implications for ability, granule secretion, and proinflammatory cytokine and health and disease. Additionally, we reveal a role for complement chemokine release (13). in homeostatic host–microbiome interactions of the skin. By using culture-independent high-throughput sequencing of bacterial 16S rRNA genes, we show that systemic inhibition of he skin is our interface to the outside world and encounters C5aR signaling leads to significant changes in the skin micro- Tcontinuous assault by foreign and potentially pathogenic biota over time, including reduced diversity and altered taxo- organisms. The skin also harbors populations of nonpathogenic, nomic composition. We also find that disrupting C5aR signaling commensal microorganisms, which have important functions in leads to decreased infiltration of the skin by inflammatory cells, skin health and disease, including colonization resistance to block invasion of opportunistic or pathogenic microbiota, and Significance regulation of immunity and inflammation (1–3). Culture- independent analyses of the healthy skin microbiota, based on Healthy skin is colonized by a diversity of microbiota. Little is sequencing of the bacterial small-subunit 16S rRNA gene, known regarding how the host immune response influences MICROBIOLOGY allow greater resolution in characterizing microbial community the skin microbiota. We demonstrate a role for complement, structure and have revealed the great topographical and temporal a key component of innate immunity, in host–microbe inter- – complexity at this barrier surface (4 8). Some environmental and actions of the skin. Inhibiting a key component of the com- fi fl host factors have been identi ed to in uence commensal skin plement cascade reduced diversity and altered composition of – microbial communities (9 12). However, the role of cutaneous the skin microbiota, parallel to a reduction in skin inflammatory immune defense in shaping and maintaining the skin microbial cell infiltration and downregulation of skin defense and im- ecosystem is currently unknown. Here, we hypothesize that com- mune gene expression. Further, we find that the commensal fl – plement, a central component of innate immunity, in uences host skin microbiota regulates the expression of complement genes microbe interactions at the skin surface. in the skin. These results suggest an interactive role between To avert microbial invasion and infection, yet simultaneously complement and the microbial ecosystem of the skin and could fl avoid damaging in ammation or autoimmunity, the host must have important implications for inflammatory and/or infectious rely upon carefully calibrated defense mechanisms at the cuta- skin disorders. neous barrier. The complement system, a network of more than 50 plasma and membrane-associated proteins, not only acts as Author contributions: J.D.L. and E.A.G. conceived the idea; C.C., S.R., J.T.S., J.D.L., and E.A.G. a first line of defense against microbes but is a key mediator designed research; C.C., S.R., A.S.T., and E.A.G. performed research; C.C., S.R., A.S.T., J.T.S., of inflammation and immune responses (13). Tight regulation of J.D.L., and E.A.G. analyzed data; and C.C., J.D.L., and E.A.G. wrote the paper. complement activation is required for the proper functioning of The authors declare no conflict of interest. the system, and, although excessive complement activation con- This article is a PNAS Direct Submission. A.J.T. is a guest editor invited by the Editorial Board. tributes to a wide variety of inflammatory and autoimmune dis- fi Data deposition: The sequence reported in this paper have been deposited in the Gen- eases (13), complement-de ciency states result in impaired host Bank database (accession no. KF501886–KF509852). defense and increased risk of infection (14). Notably, in the skin, 1To whom correspondence may be addressed. E-mail: [email protected] or lambris@ complement dysregulation, deficiency, and genetic polymorphisms upenn.edu. have been associated with a number of diseases, including pso- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. riasis, atopic dermatitis, pemphigus vulgaris, bullous pemphigoid, 1073/pnas.1307855110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1307855110 PNAS | September 10, 2013 | vol. 110 | no. 37 | 15061–15066 Downloaded by guest on September 26, 2021 and that this is accompanied by down-regulation of immune A B and defense genes in the skin, including antimicrobial peptides, PC2 (14%) PC2 (14%) cytokines and chemokines, and pattern recognition receptors. BL C5aRA Conversely, we demonstrate that the commensal skin microbiota iC5aRA regulates the expression of complement genes in the skin. Taken together, these results suggest an interactive role between com- plement and the microbial ecosystem of the skin. These findings demonstrate that cutaneous host–microbe interactions are dy- namic, and have important implications for skin disorders that incorporate microbial dysbiosis and immune dysregulation as PC1 (27%) PC1 (27%) part of their pathogenesis. Fig. 1. Antagonism of complement C5aR results in an overall change in the Results skin microbiota. Skin microbiota samples were collected from C57BL/6J mice before treatment to determine BL microbiota (purple dots), and then trea- Complement C5aR Signaling Influences the Composition and Diversity ted with C5aRA (red dots) or iC5aRA (green dots). Following a 2-wk treat- of the Skin Microbiota. To investigate the impact of complement ment course, skin microbiota were collected again to compare with BL signaling on the skin microbiome while controlling for experi- microbiota. Depicted are PCoA plots of the weighted UniFrac metric com- mental variables such as maternal transmission and environ- paring skin microbiota of (A) C5aRA-treated mice and their BL, and (B) mental influences, we used a longitudinal study design with iC5aRA-treated mice and their BL. Percentage of variation explained by the a peptide inhibitor that antagonizes C5aR (20). Before treat- principal coordinates is indicated in parentheses on the axes. Depicted is one of two independent experiments (n = 9 mice per treatment group). Table S1 ment with the C5aR antagonist (C5aRA) or an inactive control 2 (iC5aRA), C57BL/6J mice were individually housed for 2 wk and shows R and P values of the Adonis test, which assigns strength and sta- tistical significance to the sample groupings visually observed. Fig. S1 illus- skin microbiota were collected to
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