Evidence against a role for NLRP3-driven islet inflammation in db/db mice

Abstract

ObjectivesType 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D.MethodsDiabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention.ResultsMCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β.ConclusionsNLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1

“…It is entirely possible that islet macrophages exhibit a ''mixed'' pro-inflammatory and reparative phenotype in type 2 diabetes in response to phagocytosis of dead beta-cells following cell death induced by IAPP and other factors (glucose, free fatty acids, endoplasmic reticulum stress, local and/or circulating cytokines). Regardless, our findings are in agreement with a recent study in db/db mice, wherein an NLRP3 inhibitor had no effects on glycemia (Kammoun et al, 2018). Ying and colleagues also found a mixed phenotype of islet macrophages during HFD feeding, not simply defined by M1 or M2 skewing (Ying et al, 2018).…”

Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1

“…We also cannot exclude the possibility that differences in the gut microbiota may have contributed to this discrepancy, since the db/db mice in these two studies were derived from different sources. In support of our findings, a more recent study found that a potent inhibitor of NLRP3-induced IL-1β secretion had no effect on db/db disease pathogenesis (Kammoun et al, 2018). In any case, our data provide new insight into the functional state of islet macrophages in diabetes and during beta-cell death.…”

The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice

“…This impaired wound healing is observed when comparing WT mice to Ob/Ob mice, where WT mice heal within seven days and Ob/Ob mice take up to two weeks to heal wounds of the same size [ 18 ]. MCC950 has been previously described to have no effect on obesity or diabetes in a model of db/db diabetic mice [ 19 ]. Therefore, to study the effects of inflammasome-driven inflammation in chronic wound healing, the db/db model seemed ideal to test the effects of MCC950 on diabetic wounds, without affecting the diabetic phenotype itself.…”