Transcription factors that regulate monocyte subset differentiation in bone marrow have not yet been identified. Here we show that the orphan nuclear receptor NR4A1 controls Ly6C− monocyte differentiation. Ly6C− monocytes , which function in a surveillance role in circulation, were absent in Nr4a1−/− mice. Normal numbers of myeloid progenitor cells were present in Nr4a1−/− mice, indicating that the defect occurs during later stages of monocyte development. The defect is cell-intrinsic, as wild-type mice receiving bone marrow from Nr4a1−/− mice developed reduced numbers of patrolling monocytes. Ly6C− monocytes remaining in the bone marrow of Nr4a1−/− mice were arrested in the S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of differentiation and survival of ‘patrolling’ Ly6C− monocytes.

We conclude that islet macrophages are major contributors to islet IL-1β secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1β- and IL-6-mediated decreased insulin gene expression.

The global health and economic burden of type 2 diabetes (T2D) has reached staggering proportions. Current projections estimate that 592 million people will have diabetes by 2035. T2D-which comprises 90% of cases-is a complex disease, in most cases resulting from a combination of predisposing genes and an unhealthy environment. Clinical onset of the disease occurs when pancreatic β cells fail in the face of insulin resistance. It has long been appreciated that chronic activation of the innate immune system is associated with T2D, and many organs critical to the regulation of glucose homeostasis show signs of a chronic inflammatory process, including the pancreatic islets of Langerhans. Recent clinical trials using IL-1-targeting agents have confirmed that inflammation contributes to β-cell failure in humans with T2D. However, little is known about the nature of the pro-inflammatory response within the islet, and there is considerable debate about the triggers for islet inflammation, which may be systemically derived and/or tissue-specific. In this review, we present evidence that Toll-like receptors 2 and 4 and the NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3) inflammasome are triggers for islet inflammation in T2D and propose that the activation of macrophages by these triggers mediates islet endocrine cell dysfunction. Therapeutically targeting these receptors may improve hyperglycemia and protect the β cell in T2D.