Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock

Abstract

Interferon Regulatory Factor (IRF) 6, a member of the IRF family, is essential for epidermal and orofacial embryonic development. Irf6 is strongly expressed in keratinocytes, in which it regulates epidermal proliferation, differentiation, and migration. A recent role for Irf6 in Toll-like receptor 2-dependent chemokine gene expression was also reported in an epithelial cell line. However, a function for Irf6 in innate immune cells was not previously reported. In the present study, we investigated the expression and function of Irf6 in bone marrow-derived neutrophils and macrophages. We show here, using a conditional knockout of Irf6 in lysosymeM expressing cells, that Irf6 is required for resistance to LPS-induced endotoxic shock. In addition, Irf6-deficient bone marrow-derived neutrophils exhibited increased chemotactic index and velocity compared with wild-type cells in vitro. TLR4-specific KC and IL6 secretions were upregulated in Irf6-deficient bone marrow-derived macrophages in vitro. These cells also exhibited an increased level of phosphorylated IkBa. Collectively, our findings suggest a role for Irf6 in the resistance to endotoxic shock due to NFk-B-mediated alteration of cytokine production.

Interferon regulatory factor 6 is required for proper wound healing in vivo

“…No statistical difference was observed in GM‐CSF (Figure H), IL‐2 (Figure I), and IL 10 (Figure J). Globally, these results support a role for Irf6 in repressing the inflammatory response, extending our previously reported findings in endotoxic shock to tissue repair.…”

“…Here, we extended our previous findings to additional time points and demonstrated the presence of Irf6 in keratinocytes of the migrating tongue and leading edge 4 days post‐wounding (Figure A). We also observed Irf6 in the granulation tissue (Figure A), which we hypothesize are innate immune cells based on our previous findings . Seven days post‐wounding, Irf6 was restricted to the suprabasal layers of the neoformed epidermis, and occasional cells in the granulation tissue (Figure B).…”

“…Levels of VEGF and KC were also significantly elevated in Irf6 +/− 7‐day wounds compared to wild type (Figure A,F). Of note, IL‐6, which we previously showed to be upregulated in a neutrophil‐specific Irf6 conditional knockout, trended like all the other cytokines, however did not reach significance between Irf6 +/− and wild type (Figure G). No statistical difference was observed in GM‐CSF (Figure H), IL‐2 (Figure I), and IL 10 (Figure J).…”

“…The formation of the granulation tissue is dependent on the proper signaling between keratinocytes, innate immune cells, adipocytes, and fibroblasts with the requirement for the migration of collagen‐producing fibroblasts to the injured site . Although Irf6 is not detected in fibroblasts, it is expressed in both keratinocytes and innate immune cells, and has been previously reported as a repressor of inflammatory cytokines following endotoxic shock . The inflammatory phase of tissue repair is essential to the overall healing process, that must be accompanied by a return to normal levels for completion of the process .…”

“…Interferon regulatory factor (IRF) 6 is a transcription factor that belongs to the larger family of IRFs mediating the interferon response following viral infection . IRF6 is expressed in many cell types including cutaneous and oral keratinocytes, innate immune cells, and occasional myocytes and osteocytes . IRF6 belongs to a feedback loop with TP63 that regulates epidermal proliferation and differentiation .…”