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

doi:10.1016/j.isci.2023.106477

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

iScience. 2023 Mar 22;26(4):106477. doi: 10.1016/j.isci.2023.106477. eCollection 2023 Apr 21.

Authors

Le May Thai¹, Liam O'Reilly¹, Saskia Reibe-Pal¹, Nancy Sue¹, Holly Holliday¹, Lewin Small¹, Carsten Schmitz-Peiffer^{1

2

3}, Rama Dhenni¹, Vicky Wang-Wei Tsai⁴, Nicholas Norris³, Belinda Yau⁴, Xuan Zhang¹, Kailun Lee¹, Chenxu Yan¹, Yan-Chuan Shi^{1

2}, Melkam A Kebede³, Robert Brink^{1

2}, Gregory J Cooney^{1

2

3}, Katharine M Irvine⁵, Samuel N Breit^{2

4}, Tri G Phan^{1

2}, Alexander Swarbrick^{1

2}, Trevor J Biden^{1

2}

Affiliations

¹ Garvan Institute of Medical Research, Sydney, NSW, Australia.
² St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.
³ School of Medical Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
⁴ Centre for Applied Medical Research, Sydney, NSW, Australia.
⁵ Mater Research Institute-University of Queensland, Brisbane, QLD, Australia.

Abstract

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.

Keywords: Cell biology; Immunology; Physiology.