Mapping macrophage polarization over the myocardial infarction time continuum

Mouton, Alan J.; DeLeon‐Pennell, Kristine Y.; Gonzalez, O. J.; Flynn, Elizabeth R.; Freeman, Tom C.; Saucerman, Jeffrey J.; Garrett, Michael R.; Ma, Yonggang; Harmancey, Romain; Lindsey, Merry L.

doi:10.1007/s00395-018-0686-x

Cited by 223 publications

(271 citation statements)

References 96 publications

(136 reference statements)

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“…Reduced neutrophil numbers observed in female hearts after MI also protects from collateral damage incurred by neutrophil-derived mediators. While both neutrophils and macrophages use LXR/RXR signaling and are equally responsible for adverse post-MI remodeling [58, 67, 78], the neutrophil difference was prominent. Future studies that investigate the role of other immune cells, including macrophages and T and B lymphocytes, are needed to fully understand all sex differences in cardiovascular disease pathology.…”

Section: Discussionmentioning

confidence: 99%

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

et al. 2018

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Sex differences in heart failure development following myocardial infarction (MI) are not fully understood. We hypothesized that differential MI signaling could explain variations in outcomes. Analysis of the mouse heart attack research tool 1.0 (422 mice; young = 5.4 ± 0.1; old = 23.3 ± 0.1 months of age) was used to dissect MI signaling pathways, which was validated in a new cohort of mice (4.8 ± 0.2 months of age); and substantiated in humans. Plasma collected at visit 2 from the MI subset of the Jackson Heart Study (JHS; a community-based study consisting of middle aged and older adults of African ancestry) underwent glycoproteomics grouped by outcome: (1) heart failure hospitalization after visit 2 (n = 3 men/12 women) and (2) without hospitalization through 2012 (n = 24 men/21 women). Compared to young male mice, the infarct region of young females had fewer, but more efficient tissue clearing neutrophils with reduced pro-inflammatory gene expression. Apolipoprotein (Apo) F, which acts upstream of the liver X receptors/retinoid X receptor (LXR/RXR) pathway, was elevated in the day 7 infarcts of old mice compared to young controls and was increased in both men and women with heart failure. In vitro, Apo F stimulated CD36 and peroxisome proliferator-activated receptor (PPAR)γ activation in male neutrophils to turn off NF-κB activation and stimulate LXR/RXR signaling to initiate resolution. Female neutrophils were desensitized to Apo F and instead relied on thrombospondin-1 stimulation of CD36 to upregulate AMP-activated protein kinase, resulting in an overall better wound healing strategy. With age, female mice were desensitized to LXR/RXR signaling, resulting in enhanced interleukin-6 activation, a finding replicated in the JHS community cohort. This is the first report to uncover sex differences in post-MI neutrophil signaling that yielded better outcomes in young females and worse outcomes with age.Electronic supplementary materialThe online version of this article (10.1007/s00395-018-0699-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

et al. 2018

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“…Groups were randomly assigned prior to the surgeries by one investigator (KYDP) and another investigator (YM) performed the majority of surgeries. To reduce animal use as recommended by the National Centre for the Replacement, Refinement, and Reduction of Animals in Research [46], the fibroblasts used in this study were obtained from a subset of the same mice used for macrophage isolation [36]. …”

Section: Materials and Methods (Detailed Methods In Supplemental Matementioning

confidence: 99%

“…To produce permanent MI, mice underwent coronary artery ligation surgery as described previously and according to the Guidelines for Experimental Models of Ischemia and Infarction [10, 21, 24, 31, 36]. Mice were anesthetized with 2% isoflurane, intubated, and ventilated.…”

Section: Materials and Methods (Detailed Methods In Supplemental Matementioning

confidence: 99%

“…LV physiology was determined by transthoracic echocardiography (Vevo 2100, VisualSonics; Toronto, CA) as described before and according to the Guidelines for Measuring Cardiac Physiology in Mice [10, 21, 27, 31, 36]. Mice were anesthetized under 1–2% isoflurane, and both long- and short-axis images were obtained.…”

Section: Materials and Methods (Detailed Methods In Supplemental Matementioning

confidence: 99%

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Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

et al. 2019

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Cardiac fibroblasts are the major producers of extracellular matrix (ECM) to form infarct scar. We hypothesized that fibroblasts undergo a spectrum of phenotype states over the course of myocardial infarction (MI) from early onset to scar formation. Fibroblasts were isolated from the infarct region of C57BL/6J male mice (3–6 months old, n = 60) at days 0 (no MI control) and 1, 3, or 7 after MI. Whole transcriptome analysis was performed by RNA-sequencing. Of the genes sequenced, 3371 were differentially expressed after MI. Enrichment analysis revealed that MI day 1 fibroblasts displayed pro-inflammatory, leukocyte-recruiting, pro-survival, and anti-migratory phenotype through Tnfrsf9 and CD137 signaling. MI day 3 fibroblasts had a proliferative, pro-fibrotic, and pro-angiogenic profile with elevated Il4ra signaling. MI day 7 fibroblasts showed an anti-angiogenic homeostatic-like myofibroblast profile and with a step-wise increase in Acta2 expression. MI day 7 fibroblasts relied on Pik3r3 signaling to mediate Tgfb1 effects and Fgfr2 to regulate PI3K signaling. In vitro, the day 3 MI fibroblast secretome stimulated angiogenesis, while day 7 MI fibroblast secretome repressed angiogenesis through Thbs1 signaling. Our results reveal novel mechanisms for fibroblasts in expressing pro-inflammatory molecules and regulating angiogenesis following MI.Electronic supplementary materialThe online version of this article (10.1007/s00395-019-0715-4) contains supplementary material, which is available to authorized users.

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“…Mouton et al analyzed macrophage physiology over the duration of MI, determining that macrophages isolated from mice 3 days post-MI exhibited an enriched phagocytic and proliferative phenotype [129]. A depletion of MertK, a specific marker of phagocytosis, correlates with prolonged inflammations due to an insufficient clearance of apoptotic cells [196].…”

Section: Strategies For Therapeutic Interventions That Target Immunementioning

confidence: 99%

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

2018

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Myocardial infarction triggers infiltration of several types of immune cells that coordinate both innate and adaptive immune responses. These play a dual role in post-infarction cardiac remodeling by initiating and resolving inflammatory processes, which needs to occur in a timely and well-orchestrated way to ensure a reestablishment of normalized cardiac functions. Thus, therapeutic modulation of immune responses might have benefits for infarct patients. While such strategies have shown great potential in treating cancer, applications in the post-infarction context have been disappointing. One challenge has been the complexity and plasticity of immune cells and their functions in cardiac regulation and healing. The types appear in patterns that are temporally and spatially distinct, while influencing each other and the surrounding tissue. A comprehensive understanding of the immune cell repertoire and their regulatory functions following infarction is sorely needed. Processes of cardiac remodeling trigger additional genetic changes that may also play critical roles in the aftermath of cardiovascular disease. Some of these changes involve non-coding RNAs that play crucial roles in the regulation of immune cells and may, therefore, be of therapeutic interest. This review summarizes what is currently known about the functions of immune cells and non-coding RNAs during post-infarction wound healing. We address some of the challenges that remain and describe novel therapeutic approaches under development that are based on regulating immune responses through non-coding RNAs in the aftermath of the disease.

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Mapping macrophage polarization over the myocardial infarction time continuum

Cited by 223 publications

References 96 publications

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

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