IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation

Abstract

Inflammation resolution is important for scar formation following myocardial infarction (MI) and requires the coordinated actions of macrophages and fibroblasts. In this study, we hypothesized that exogenous interleukin-10 (IL-10), an anti-inflammatory cytokine, promotes post-MI repair through actions on these cardiac cell types. To test this hypothesis, C57BL/6J mice (male, 3- to 6-month old, n = 24/group) were treated with saline or IL-10 (50 μg/kg/day) by osmotic mini-pump infusion starting at day (d) 1 post-MI and sacrificed at d7 post-MI. IL-10 infusion doubled plasma IL-10 concentrations by d7 post-MI. Despite similar infarct areas and mortality rates, IL-10 treatment significantly decreased LV dilation (1.6-fold for end-systolic volume and 1.4-fold for end-diastolic volume) and improved ejection fraction 1.8-fold (both p < 0.05). IL-10 treatment attenuated inflammation at d7 post-MI, evidenced by decreased numbers of Mac-3+ macrophages in the infarct (p < 0.05). LV macrophages isolated from d7 post-MI mice treated with IL-10 showed significantly elevated gene expression of M2 markers (Arg1, Ym1, and TGF-β1; all p < 0.05). We further performed RNA-seq analysis on post-MI cardiac macrophages and identified 410 significantly different genes (155 increased, 225 decreased by IL-10 treatment). By functional network analysis grouping, the majority of genes (133 out of 410) were part of the cellular assembly and repair functional group. Of these, hyaluronidase 3 (Hyal3) is the most important feature identified by p value. IL-10 treatment decreased Hyal3 by 28%, which reduced hyaluronan degradation and limited collagen deposition (all p < 0.05). In addition, ex vivo IL-10 treatment increased fibroblast activation (proliferation, migration, and collagen production), an effect that was both directly and indirectly influenced by macrophage M2 polarization. Combined, our results indicate that in vivo infusion of IL-10 post-MI improves the LV microenvironment to dampen inflammation and facilitate cardiac wound healing.

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

“…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.…”

“…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.…”

“…LV fibroblasts were isolated from the infarct by immunomagnetic separation as described previously [10, 21, 36]. Excised LV tissue was rinsed and immediately minced and digested by collagenase II (Worthington; Lakewood, NJ) and DNase solution in Hanks-buffered saline solution.…”

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

“…The inflammatory response post-MI can result in systemic atherosclerosis with elevated numbers of macrophage-derived foam cells accompanied by enhanced lipid metabolism [85]. LncRNA E330013P06 is expressed at high levels in foam cells, a phenomenon associated with exaggerated cardiac inflammation.…”

Improvements in long standing cardiac pathologies by individualized homeopathic remedies: A case series

“…The continued discovery of factors involved in the remodelling of an infarcted heart pose continuous challenges. The latest available therapeutic options include the following: interleukin 10 (IL-10), 11 calcium-activated potassium channel (KCa3.1) blocking, 12 basic fibroblast growth factor with the transplantation of stem cells from fat tissue 13 and regenerative cell therapy 14,15 but also berberine therapy, 16 lycopene supplementation, 17 continuous normobaric hypoxia, 18 repeated controlled ischaemia 19 and so on.…”