TNFR2 induced priming of NLRP3-inflammasome via RIPK1 leads to pyroptosis in XIAP deficient cells

Abstract

Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap -/macrophages. Yet, the direct role TNFR2specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation lead to cell death in xiap -/myeloid cells, particularly in the absence the RING domain. RIPK1/TAK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death independent of necroptosis. TNFR2-specific activation lead to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of up-regulation of NLRP3 and caspase-11. Activation and up-regulation of the canonical inflammasome was mediated by RIPK1 kinase activity and ROS production. While both RIPK1 kinase activity and ROS production reduced cell death as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports, targeting TNFR2 specifically to reduce IL-18 release in XIAP deficient (XLP-2) patients.

Pyroptosis: The missing puzzle among innate and adaptive immunity crosstalk

“…X‐linked inhibitor of apoptosis (XIAP) deficient mice macrophages underwent pyroptosis via NLRP3‐inflammasome induction by TNFR2. These cells exhibited an increase of CCL2, CCL3, CCL4, CXCL1, CXCL2, CCL11, IL‐1β, IL‐6, and IL‐18 184 …”

Tumor cell-derived lymphotoxin alpha triggers metastatic extravasation through TNFRs/cIAP1

“…NF-κB drives TNF production and in the absence of cIAP1, TNFR1 activation leads to the formation of complex II and subsequent cell death (8)(9)(10)(11). TNFR2 activation in the absence of IAPs also induces cell death through a TNF/TNFR1 mechanism (12,13).…”