ZFIN ID: ZDB-PUB-201229-4
RIPK3-mediated inflammation is a conserved β cell response to ER stress
Yang, B., Maddison, L.A., Zaborska, K.E., Dai, C., Yin, L., Tang, Z., Zang, L., Jacobson, D.A., Powers, A.C., Chen, W.
Date: 2020
Source: Science advances   6(51): (Journal)
Registered Authors: Chen, Wenbiao
Keywords: none
MeSH Terms: none
PubMed: 33355143 Full text @ Sci Adv
Islet inflammation is an important etiopathology of type 2 diabetes; however, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered RIPK3-dependent IL1B induction in β cells as an instigator of islet inflammation. In cultured β cells, ER stress activated RIPK3, leading to NF-kB-mediated proinflammatory gene expression. In a zebrafish muscle insulin resistance model, overnutrition caused islet inflammation, β cell dysfunction, and loss in an ER stress-, ripk3-, and il1b-dependent manner. In mouse islets, high-fat diet triggered the IL1B expression in β cells before macrophage recruitment in vivo, and RIPK3 inhibition suppressed palmitate-induced β cell dysfunction and Il1b expression in vitro. Furthermore, in human islets grafted in hyperglycemic mice, a marked increase in ER stress, RIPK3, and NF-kB activation in β cells were accompanied with murine macrophage infiltration. Thus, RIPK3-mediated induction of proinflammatory mediators is a conserved, previously unrecognized β cell response to metabolic stress and a mediator of the ensuing islet inflammation.