Particle and Fibre Toxicology · 10 authors, 5 centres
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Oral administration of diesel exhaust particles to mice for up to 10 months induced glucose intolerance via an intestinal macrophage inflammatory response involving NLRP3 and IL-1β signaling. Genetic or pharmacological depletion of macrophages, NLRP3, or IL-1β protected mice from DEP-induced glucose intolerance.
Wild-type mice were exposed to DEP or PBS via oral gavage for up to 10 months. RNA-sequencing of intestinal macrophages revealed an interferon and inflammatory signature with a decrease of CCR2− anti-inflammatory/resident macrophages. Depletion of macrophages using CSF1R inhibition, genetic NLRP3 deletion, or anti-IL-1β treatment protected mice from DEP-induced glucose intolerance. In contrast, Rag2-/- mice lacking adaptive immune cells developed glucose intolerance after just one month of DEP exposure, faster than wild-type mice. In vitro experiments confirmed that DEP enhanced IL-1β secretion in macrophages, which was attenuated by NLRP3 depletion. Limitations include that findings are restricted to gut exposure only, the cues driving macrophage changes are unresolved, and the cross-talk mechanism between intestinal macrophages and pancreatic islets remains unclear.
