Key Points

FasL-treated macrophages display proteolytic cleavage of the gasdermin family.

TAK1 functions as a negative regulator of Fas signaling in macrophages.

TAK1 in macrophages protects mice from spontaneous tissue inflammation.

Abstract

Fas, a member of the death receptor family, plays a central role in initiating cell death, a biological process crucial for immune homeostasis. However, the immunological and pathophysiological impacts to which enhanced Fas signaling gives rise remain to be fully understood. Here we demonstrate that TGF-β–activated kinase 1 (TAK1) works as a negative regulator of Fas signaling in macrophages. Upon Fas engagement with high concentrations of FasL, mouse primary macrophages underwent cell death, and, surprisingly, Fas stimulation led to proteolytic cleavage of gasdermin (GSDM) family members GSDMD and GSDME, a hallmark of pyroptosis, in a manner dependent on caspase enzymatic activity. Remarkably, TAK1-deficient macrophages were highly sensitive to even low concentrations of FasL. Mechanistically, TAK1 negatively modulated RIPK1 kinase activity to protect macrophages from excessive cell death. Intriguingly, mice deficient for TAK1 in macrophages (TAK1mKO mice) spontaneously developed tissue inflammation, and, more important, the emergence of inflammatory disease symptoms was markedly diminished in TAK1mKO mice harboring a catalytically inactive RIPK1. Taken together, these findings not only revealed an unappreciated role of TAK1 in Fas-induced macrophage death but provided insight into the possibility of perturbation of immune homeostasis driven by aberrant cell death.

Footnotes

This work was supported by Japan Society for the Promotion of Science KAKENHI Grant JP21K06868 and Kobayashi International Scholarship Foundation (H.S.).

The online version of this article contains supplemental material.

Abbreviations used in this article:

BMDMbone marrow–derived macrophagec-FLIPLfull-length c-FLIPGSDMDgasdermin DHMGB1high mobility group box 1LDHlactate dehydrogenaseLPMlarge peritoneal macrophageMLKLmixed lineage kinase domain-like proteinPARPpoly(ADP-ribose) polymeraseRIPK1receptor-interacting serine/threonine-protein kinase 1SPFspecific pathogen-freeTAK1TGF-β–activated kinase 1TNFRTNF receptorTRIFToll/IL-1R (TIR) domain-containing adapter inducing IFN-βReceived May 2, 2022.Accepted July 11, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.