TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP

Abstract

The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap−/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap−/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of 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 XLP-2 patients and to reduce priming of the inflammasome components.

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

“…TRAF2 is vital for preventing RIPK1-mediated apoptosis. In addition, TRAF2 rapidly undergoes proteasomal degradation following stimulation of RIPK1-deficient hepatocytes and embryonic fibroblasts via a caspase-independent necrotic cell death mechanism [40]. Also, the physical scaffold of RIPK1 on complex I prevented the proteasomal degradation of TRAF2 [41].…”

Evolution of Our Understanding of XIAP Deficiency

“…Furthermore, XIAP is important in regulating the activation of the NLRP3 inflammasome (Figure 3B). XIAP loss results in dysregulation of classical caspase-1/NLRP3 inflammasome activation, overproduction of pro-inflammatory cytokines and cell death (6,40,48,50,(54)(55)(56)(57). First described was the inhibitory effect XIAP has on the ripoptosome, a death-inducing complex comprised of RIKP1, FADD and caspase-8, following both TNFR1 and TLR signalling.…”

Targeting RIP Kinases in Chronic Inflammatory Disease

“…Likewise, RIPK1 can act as a repressor of RIPK3/MLKL-mediated necroptotic activation of NLRP3 [ 45 ]. Additionally, TLR4-TRIF (or TNFR) signalling in IAP-depleted myeloid cells can induce the direct caspase-8-mediated proteolysis of IL-1β, as well as NLRP3 inflammasome activation that is dependent on K + efflux linked to caspase-8-mediated apoptosis occurring upstream [ 45 , 78 , 88 ].…”