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
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.
