β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling

Le May Thai; Liam O’Reilly; Saskia Reibe-Pal; Nancy Sue; Holly Holliday; Lewin Small; Carsten Schmitz-Peiffer; Rama Dhenni; Vicky Wang-Wei Tsai; Nicholas Norris; Belinda Yau; Xuan Zhang; Kailun Lee; Chenxu Yan; Yan-Chuan Shi; Melkam A. Kebede; Robert Brink; Gregory J. Cooney; Katharine M. Irvine; Samuel N. Breit; Tri G. Phan; Alexander Swarbrick; Trevor J. Biden

iScience (Apr 2023)

β-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFβ receptor signaling

Le May Thai,
Liam O’Reilly,
Saskia Reibe-Pal,
Nancy Sue,
Holly Holliday,
Lewin Small,
Carsten Schmitz-Peiffer,
Rama Dhenni,
Vicky Wang-Wei Tsai,
Nicholas Norris,
Belinda Yau,
Xuan Zhang,
Kailun Lee,
Chenxu Yan,
Yan-Chuan Shi,
Melkam A. Kebede,
Robert Brink,
Gregory J. Cooney,
Katharine M. Irvine,
Samuel N. Breit,
Tri G. Phan,
Alexander Swarbrick,
Trevor J. Biden

Affiliations

Le May Thai: Garvan Institute of Medical Research, Sydney, NSW, Australia
Liam O’Reilly: Garvan Institute of Medical Research, Sydney, NSW, Australia
Saskia Reibe-Pal: Garvan Institute of Medical Research, Sydney, NSW, Australia
Nancy Sue: Garvan Institute of Medical Research, Sydney, NSW, Australia
Holly Holliday: Garvan Institute of Medical Research, Sydney, NSW, Australia
Lewin Small: Garvan Institute of Medical Research, Sydney, NSW, Australia
Carsten Schmitz-Peiffer: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Rama Dhenni: Garvan Institute of Medical Research, Sydney, NSW, Australia
Vicky Wang-Wei Tsai: Centre for Applied Medical Research, Sydney, NSW, Australia
Nicholas Norris: School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Belinda Yau: Centre for Applied Medical Research, Sydney, NSW, Australia
Xuan Zhang: Garvan Institute of Medical Research, Sydney, NSW, Australia
Kailun Lee: Garvan Institute of Medical Research, Sydney, NSW, Australia
Chenxu Yan: Garvan Institute of Medical Research, Sydney, NSW, Australia
Yan-Chuan Shi: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
Melkam A. Kebede: School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Robert Brink: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
Gregory J. Cooney: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Katharine M. Irvine: Mater Research Institute-University of Queensland, Brisbane, QLD, Australia
Samuel N. Breit: St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; Centre for Applied Medical Research, Sydney, NSW, Australia
Tri G. Phan: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
Alexander Swarbrick: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
Trevor J. Biden: Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; Corresponding author

Journal volume & issue: Vol. 26, no. 4
p. 106477

Abstract

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Summary: We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue remodeling) polarization. Under steady state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodeling via the metabolically regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and TGFβ receptor signaling. This impairs GSIS and potentially contributes to β-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving β-cell function during metabolic disease.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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