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Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction
Shanshan Cai, … , Jennifer Davis, Rong Tian
Shanshan Cai, … , Jennifer Davis, Rong Tian
Published December 8, 2022
Citation Information: J Clin Invest. 2023;133(4):e159498. https://doi.org/10.1172/JCI159498.
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Research Article Cardiology Metabolism

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

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Abstract

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3–7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

Authors

Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian

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Figure 6

Mitochondria-targeted ROS scavenging improves macrophage function and reduces mortality in mKO mice after MI.

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Mitochondria-targeted ROS scavenging improves macrophage function and re...
(A and B) Apoptotic RBCs were labeled with CFDA-SE and cocultured with mKO BMDMs (±1 μM mtT) for 3 hours. Representative histograms of total CFDA-SE+ cell counts (A) and quantitation of phagocytic macrophages (B) (n = 5/group). **P < 0.01, by 2-tailed Student’s t test. (C–H) mRNA levels in mKO BMDMs after mtT (1 μM) or vehicle treatment and coculturing with or without apoptotic RBCs for 8 hours. All values are presented as the fold change relative to untreated control BMDMs. Dashed lines indicate mRNA levels in the control BMDMs cocultured with apoptotic RBCs. Data are shown as the mean ± SEM. All experiments were repeated in BMDMs from 4–5 mice per group. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-way ANOVA. (I) Survival rates of mKO mice with or without administration of mito-TEMPO (10 mg/kg day) out to post-MI day 7. *P < 0.05, by Gehan–Breslow–Wilcoxon test. (J) Cardiac rupture rate during the first 7 days after MI. (K) Representative immunofluorescence images of cardiac myofibroblast proliferation at post-MI day 3. Proliferating myofibroblasts were identified (white arrows) as PDGFRα+ (green) and EdU+ (pink). Nuclei are stained with Hoechst (blue). Scale bar: 25 μm. (L) Quantitation of PDGFRα+ and EdU+ cells as a percentage of total PDGFRα+ cells in the infarcted region (n = 4–5/group). Dots represent biological replicates, and data represent the mean ± SEM. (M) Immunofluorescence images of fibronectin in infarcted heart tissue at post-MI day 7. Scale bars: 25 μm. (N) Quantitative morphometry of immunostaining, in which the relative abundance of the stained area was calculated by averaging the results from multiple independent images of heart sections (n = 4/group). (O) Representative immunofluorescence images of α-SMA in the infarcted heart section at post-MI day 7: fibronectin (red), α-SMA (green), and Hoechst (blue). Scale bars: 50 μm. (P) Quantification of α-SMA+ levels in heart tissue at post-MI day 7 (n = 4/group). Dots represent biological replicates, and data represent the mean ± SEM.

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