| First Author | Malireddi RKS | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 4 | Pages | 1023-1034 |
| PubMed ID | 29500178 | Mgi Jnum | J:261598 |
| Mgi Id | MGI:6155845 | Doi | 10.1084/jem.20171922 |
| Citation | Malireddi RKS, et al. (2018) TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J Exp Med 215(4):1023-1034 |
| abstractText | The NOD-like receptor (NLR)-P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-beta activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis. Autocrine tumor necrosis factor (TNF) signaling in the absence of TAK1 induced spontaneous RIPK1-dependent NLRP3 inflammasome activation and cell death. We further showed that TAK1 suppressed homeostatic NF-kappaB and extracellular signal-related kinase (ERK) activation to limit spontaneous TNF production. Moreover, the spontaneous inflammation resulting from TAK1-deficient macrophages drives myeloid proliferation in mice, and was rescued by RIPK1 deficiency. Overall, these studies identify a critical role for TAK1 in maintaining NLRP3 inflammasome quiescence and preserving cellular homeostasis and survival. |
