Distinct Kinase-Independent Role of RIPK3 in CD11c+ Mononuclear Phagocytes in Cytokine-Induced Tissue Repair

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): Kenta Moriwaki, Sakthi Balaji, John Bertin, Peter J. Gough, Francis Ka-Ming Chan
Receptor interacting protein kinase 3 (RIPK3) induces necroptosis, a type of regulated necrosis, through its kinase domain and receptor interacting protein (RIP) homotypic interaction motif (RHIM). In addition, RIPK3 has been shown to regulate NLRP3 inflammasome and nuclear factor κB (NF-κB) activation. However, the relative contribution of these signaling pathways to RIPK3-dependent inflammation in distinct immune effectors is unknown. To investigate these questions, we generated RIPK3-GFP reporter mice. We found that colonic CD11c⁺CD11b⁺CD14⁺ mononuclear phagocytes (MNPs) expressed the highest level of RIPK3 in the lamina propria. Consequently, deletion of the RIPK3 RHIM in CD11c⁺ cells alone was sufficient to impair dextran sodium sulfate (DSS)-induced interleukin (IL)-23 and IL-1β expression, leading to severe intestinal inflammation. In contrast, mice expressing kinase inactive RIPK3 were not hypersensitive to DSS. Thus, a key physiological function of RIPK3 is to promote reparative cytokine expression through intestinal CD11c⁺ MNPs in a kinase- and necroptosis-independent manner.

Graphical abstract

Teaser

Moriwaki et al. demonstrate that RIPK3 promotes cytokine production in CD11c⁺ mononuclear phagocytes in an RHIM-dependent, but kinase-independent manner. This necroptosis-independent function of RIPK3 is crucial for tissue repair in response to intestinal injury.


http://ift.tt/2lVkuZT