TY - JOUR
T1 - Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury
AU - DeBerge, Matthew
AU - Glinton, Kristofor
AU - Lantz, Connor
AU - Ge, Zhi-Dong
AU - Sullivan, David P
AU - Patil, Swapna
AU - Lee, Bo Ryung
AU - Thorp, Minori I.
AU - Mullick, Adam
AU - Yeh, Steve
AU - Han, Shuling
AU - van der Laan, Anja M.
AU - Niessen, Hans W.M.
AU - Luo, Xunrong
AU - Sibinga, Nicholas E.S.
AU - Thorp, Edward B.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2025
Y1 - 2025
N2 - Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species–dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.
AB - Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species–dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.
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U2 - 10.1038/s44161-024-00585-y
DO - 10.1038/s44161-024-00585-y
M3 - Article
C2 - 39747455
AN - SCOPUS:85213868580
SN - 2731-0590
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
M1 - e001993
ER -