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Islet macrophages as integral regulators of islet inflammation, beta-cell function and survival

University of British Columbia

Pancreatic islet inflammation and beta-cell death are features of type 2 diabetes, contributing to inadequate insulin secretion and hyperglycemia. Macrophages, innate immune cells, form a dispersed homeostatic organ found in most mammalian tissues, including insulin-producing islets. Macrophages act as local sentinel cells that can either contribute to the pro-inflammatory milieu of the islet or support beta-cell proliferation in mouse models of beta-cell regeneration. They constantly monitor their surroundings and are able to uptake particles from the blood. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in people who are newly diagnosed with type 2 diabetes and activation of TLRs facilitates proinflammatory responses in macrophages. Conversely, apoptotic cells promote a tissue repair program in macrophages, and apoptosis is thought to be the main mechanism of beta-cell death in type 2 diabetes. Thus, based on the hypothesis that the polarization of islet macrophages is adaptively shaped by changes in their microenvironment and has functional consequences on beta cells, this study was designed to evaluate the physiology of islet macrophages and beta cells in two settings: first, in response to TLR2/6- and TLR4- ligands, and secondly, following beta-cell death. Genetic and pharmacological approaches were used to thoroughly characterize islet macrophages from C57BL/6J, TLR2- and TLR4-deficient, streptozotocin (STZ)-treated, high-fat diet (HFD)-STZ-treated, and db/db mice. Macrophages were found to be major contributors to human islet IL-1β secretion in response to TLR2/6 and TLR4 ligands and reduced insulin secretion from mouse pancreatic beta cells, partly via IL-1- and IL-6-mediated decrease in insulin gene expression. Following STZ-induced beta-cell death, in diabetic db/db, and HFD+STZ mice, islet macrophages acquired a reparative state characterized by enhanced Igf1, and decreased proinflammatory cytokine expression. Depletion and adoptive transfer experiments indicated a role for macrophages in regulating insulin secretion in vivo, and IGF-1 neutralization during STZ-treatment decreased insulin secretion without affecting islet-cell turnover. Importantly, macrophages were still in a reparative state even when beta-cell death occurred during HFD feeding or severe hyperglycemia. Overall, these data may have implications for islet pathophysiology in type 2 diabetes and suggest that islet macrophages could be manipulated to either induce or resolve islet inflammation.

Text

2020-04-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74113

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/