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Secretory functions of macrophages in the human pancreatic islet are regulated by endogenous purinergic signaling

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posted on 24.04.2020 by Ada Admin, Jonathan R. Weitz, Carol Jacques-Silva, Mirza Muhammed Fahd Qadir, Oliver Umland, Elizabeth Pereira, Farhan Qureshi, Alejandro Tamayo, Juan Dominguez-Bendala, Rayner Rodriguez-Diaz, Joana Almaça, Alejandro Caicedo
Endocrine cells of the pancreatic islet interact with their microenvironment to maintain tissue homeostasis. Communication with local macrophages is particularly important in this context, but the homeostatic functions of human islet macrophages are not known. Here we show that the human islet contains macrophages in perivascular regions that are the main local source of the anti-inflammatory cytokine Il-10 and the metalloproteinase MMP9. Macrophage production and secretion of these homeostatic factors is controlled by endogenous purinergic signals. In obese and diabetic states, macrophage expression of purinergic receptors, MMP9, and Il-10 is reduced. We propose that in those states exacerbated beta cell activity due to increased insulin demand and increased cell death produces high levels of ATP that downregulate purinergic receptor expression. Loss of ATP sensing in macrophages may reduce their secretory capacity.

Funding

This work was supported by the Diabetes Research Institute Foundation and National Institutes of Health grants R56DK084321 (AC), R01DK084321 (AC), R01DK111538 (AC), R01DK113093 (AC), U01DK120456 (AC) R33ES025673 (AC) and R21ES025673 (AC), the Leona M. and Harry B. Helmsley Charitable Trust grants G-2018PG-T1D034 and G-1912-03552, and by the American Heart Association 19POST34450054 (JRW).

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