Border Security: The Role of RIPK3 in Epithelium Homeostasis.

Francis Ka-Ming Chan,Sakthi Balaji,Kenta Moriwaki

doi:10.3389/fcell.2016.00070

Abstract

Receptor interacting protein kinase 3 (RIPK3) is a crucial inducer of necroptosis. Its activity is controlled by interaction with other signal adaptors through the “RIP homotypic interaction motif” (RHIM). Recent studies revealed a critical function for RIPK3 in the maintenance of epithelial tissue integrity. In mice with genetic deficiency of the apoptosis adaptors FADD or caspase 8, RIPK3 promotes necroptotic cell death of epithelial cells, leading to excessive and lethal inflammation. In contrast, when FADD and caspase 8 functions are intact, RIPK3 serves as a protector of intestinal epithelial integrity by promoting injury-induced wound repair. In the latter case, RIPK3 promotes optimal cytokine expression by cells of hematopoietic origin. Specifically, bone marrow derived dendritic cells (BMDCs) have an obligate requirement for RIPK3 for optimal secretion of mature IL-1β and other inflammatory cytokines in response to toll-like receptor 4 (TLR4) stimulation. RIPK3 promotes cytokine expression through two complementary mechanisms: NF-κB dependent gene transcription and processing of pro-IL-1β. We propose that RIPK3 functions in different cell compartments to mediate inflammation through distinct mechanisms.

Highlights

Epithelial tissues are the first lines of defense against pathogens and environmental insults
Because of the severe diarrhea and body weight loss in the antibiotics-treated mice, all the animals had to be euthanized on day 9. These results suggest that Receptor interacting protein kinase 3 (RIPK3) may facilitate sensing of specific bacterial pathogen-associated molecular patterns (PAMPs)
Intestinal epithelial cell (IEC) proliferation was severely impaired in Ripk3−/− mice (Moriwaki et al, 2014), indicating that RIPK3 protects against dextran sodium sulfate (DSS)-induced injury through promoting intestinal epithelial cell (IEC) regeneration and tissue repair

Summary

INTRODUCTION

Epithelial tissues are the first lines of defense against pathogens and environmental insults. Intestinal epithelial cell (IEC) proliferation was severely impaired in Ripk3−/− mice (Moriwaki et al, 2014), indicating that RIPK3 protects against DSS-induced injury through promoting IEC regeneration and tissue repair. We cannot rule out contribution from other inflammatory mediators, these results are consistent with the notion that chronic injury caused by RIPK3 deficiency eventually led to sustained production of inflammatory cytokines in Ripk3−/− mice In this regard, it is interesting to note that elevated RIPK3 expression was detected in human patients of inflammatory bowel diseases (Pierdomenico et al, 2014). Besides NF-κB dependent cytokine gene expression, RIPK3 is an important factor for pro-IL-1β processing, a function that is critical for optimal IL-1β expression in response to DSS-induced intestinal injury. RIPK1 provides a “survival scaffold” that counteracts the deleterious effects of RIPK3 through other yet-to-be defined mechanisms

CONCLUSION

Findings

MATERIALS AND METHODS