Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity

Abstract

The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Modelling host-Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids

“…Bulk transcriptomics has enabled us to identify that the brain organoids specifically respond to T. brucei gambiense in vitro by upregulating several genes with putative immune functions such as CXCL14, the alarmin IL33, the complement component C4B, as well as vasculogenesis and vascular repair such as VEGFC, and EPCAM. CXCL14 is a potent antimicrobial cytokine secreted in response to inflammatory processes and is critical for human neutrophil recruitment, 14,16,17 which have been proposed as important players in controlling CNS infections. 18,19 Similarly, the upregulation of several genes critical for angiogenesis and development of vascular beds, including VEGFA, VEGFB, and VWF, suggests that they may potentially support vasculogenesis in the presence of this pathogen.…”

Modelling host-Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids

“…Bulk transcriptomics has enabled us to identify that the brain organoids specifically respond to T. brucei gambiense in vitro by upregulating several genes with putative immune functions such as CXCL14 , the alarmin IL33 , the complement component C4B , as well as vasculogenesis and vascular repair such as VEGFC . CXCL14 is a potent antimicrobial cytokine secreted in response to inflammatory processes and is critical for human neutrophil recruitment, 14 , 16 , 17 which have been proposed as important players in controlling CNS infections. 18 , 19 Similarly, the upregulation of several genes critical for angiogenesis and development of vascular beds, including VEGFA, VEGFB , and VWF , suggests that they may potentially support vasculogenesis in the presence of this pathogen.…”

How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells

“… 52 Epidermal keratinocytes produce the chemokine CXCL14 in a circadian pattern, which suppresses skin bacterial proliferation in a diurnal manner through the regulation of the innate immune system. 67 The migration of dermal dendritic cells into lymphatic vessels is under the control of the chemokine CCL21 and adhesion molecules, which in turn are directly regulated by the circadian clock. 68 …”