Complement modulates the cutaneous microbiome and inflammatory milieu

Abstract

The skin is colonized by a plethora of microbes that include commensals and potential pathogens, but it is currently unknown how cutaneous host immune mechanisms influence the composition, diversity, and quantity of the skin microbiota. Here we reveal an interactive role for complement in cutaneous host-microbiome interactions. Inhibiting signaling of the complement component C5a receptor (C5aR) altered the composition and diversity of the skin microbiota as revealed by deep sequencing of the bacterial 16S rRNA gene. In parallel, we demonstrate that C5aR inhibition results in down-regulation of genes encoding cutaneous antimicrobial peptides, pattern recognition receptors, and proinflammatory mediators. Immunohistochemistry of inflammatory cell infiltrates in the skin showed reduced numbers of macrophages and lymphocytes with C5aR inhibition. Further, comparing cutaneous gene expression in germ-free mice vs. conventionally raised mice suggests that the commensal microbiota regulates expression of complement genes in the skin. These findings demonstrate a component of host immunity that impacts colonization of the skin by the commensal microbiota and vice versa, a critical step toward understanding hostmicrobe immune mutualism of the skin and its implications for health and disease. Additionally, we reveal a role for complement in homeostatic host-microbiome interactions of the skin.

Distinct Roles of the Anaphylatoxins C3a and C5a in Dendritic Cell–Mediated Allergic Asthma

“…It is well appreciated that identical mouse strains can differ significantly in their microbiome composition depending on their housing conditions and that such differences have a strong impact on the emergence of particular CD4 + T cell subsets, in particular with regard to the development of Th17 cells (57). In support of this view, C5aR1 signaling has been shown to modulate the cutaneous microbiome, which was associated with alterations in innate and adaptive immune cells in the skin (58). Similarly, we observed an altered composition and diversity of the intestinal microbiome of C5aR1 2/2 mice as compared with WT littermates (J. Köhl, unpublished observation).…”

The intersection of microbiome and host at the skin interface: genomic- and metagenomic-based insights

“…Indeed, colonization with a human commensal skin microbe, namely, Staphylococcus epidermidis, tunes T-cell homing and function in an IL-1-dependent manner in mice (Naik et al 2012(Naik et al , 2015. On the other hand, deficiencies in immunity have been shown in humans and mice to result in altered cutaneous microbial communities (Chehoud et al 2013;Oh et al 2013). Thus it appears that cutaneous microbial communities are intimately linked with skin innate and adaptive immune functions.…”

Microbial Ecology of the Skin in the Era of Metagenomics and Molecular Microbiology

“…For example, the skin commensal Staphylococcus epidermidis has been reported to modulate the innate immune response by inhibiting skin inflammation through pattern-recognition receptor-mediated cross talk (Lai et al 2009). Complement, an evolutionarily conserved arm of the innate immune system, was shown to maintain diversity of the skin microbiota in a mouse model, and, conversely, the skin microbiota regulated complement at the gene expression level (Chehoud et al 2013). The microbiome is also fundamental in adaptive immune system equilibrium at the skin, and skin T-cell function and the local inflammatory milieu appear to be autonomously controlled by the commensal skin microbiota (Naik et al 2012).…”