Interleukin-23 Deficiency Leads to Impaired Wound Healing and Adverse Prognosis After Myocardial Infarction

Abstract

Background-CD4+ cells are implicated in the healing process after myocardial infarction (MI). We sought to investigate the role of interleukin-23 (IL-23) deficiency, a cytokine important in differentiation of CD4+ cells, in scar formation of the ischemic heart. Methods and Results-MI was performed in wild-type and IL23p19−/− mice. Thirty-day mortality, hemodynamic function 4 days after MI and myocardial inflammation, and remodeling 4 and 30 days after MI were examined. Differentiation of fibroblasts from infarcted and noninfarcted hearts into myofibroblasts was examined under basal conditions and after stimulation with interferon-γ, IL-17α and IL-23. Interleukin-23p19−/− mice showed higher expression of proinflammatory cytokines and immune cell infiltration in the scar early after MI compared with wild-type mice. A stronger interferon-γ/ Th1 reaction seemed to be responsible for the increased inflammation under IL-23 deficiency. Expression of α-smooth muscle actin (α-SMA), collagen I and III was significantly higher in the heart tissue and isolated cardiac fibroblasts 4 days after MI in the wild-type mice. Interleukin-23p19−/− mice showed impaired healing compared with wild-type mice, as seen by significantly higher mortality because of ventricular rupture (40% higher after 30 days) and stronger left ventricular dilation early after MI. Stimulation of cardiac fibroblasts with interferon-γ, the main Th1 cytokine, but not with IL-23 or IL-17α, led to a significant downregulation of α-smooth muscle actin, collagen I and III and decreased migration and differentiation to myofibroblasts. Conclusions-IL-23 deficiency leads to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired scar formation and adverse remodeling after MI. (Circ Heart Fail. 2014;7:161-171.)

IL-17 and Th17 Cells in Atherosclerosis

“…IL-23 deficiency led to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired remodeling after MI, suggesting protective roles for IL-23 and IL-17 in MI. 73 It is interesting to note that in that study, IL-23 deficiency, through reduced IL-17 production, was able to suppress the deleterious Th1/IFN-γ response in the early stages after MI, thus reducing excessive myocardial inflammation. 73 However, in another study, Yan et al 72 reported a protective effect of IL-23 deficiency after MI, associated with no change of IFN-γ production and decreased myocardial inflammation.…”

“…73 It is interesting to note that in that study, IL-23 deficiency, through reduced IL-17 production, was able to suppress the deleterious Th1/IFN-γ response in the early stages after MI, thus reducing excessive myocardial inflammation. 73 However, in another study, Yan et al 72 reported a protective effect of IL-23 deficiency after MI, associated with no change of IFN-γ production and decreased myocardial inflammation. These discrepancies need to be addressed in future studies and may result from differences in mouse background and the study of different time courses after MI.…”

Chronic Heart Failure and Inflammation

“…IL-23 is an inducer of IL-17A, and loss of IL-23 (and presumably IL-17A) can impair tissue fibrosis-which can be pathological in some scenarios. 156,157 As reviewed elsewhere, 17 IL-17A can drive inflammation through several pathways, including being directly toxic to cardiomyocytes, 158 and can also drive production of neutrophils in the bone marrow, which can later infiltrate the myocardium. 159 In addition to being produced by Th17 cells, IL-17A can also be produced by innate γδ T cells and neutrophils themselves.…”

Left Ventricular Remodeling after Acute Myocardial Infarction and Biomarkers

“…In addition, new studies by Hofmann et al and Savvatis et al, showed that inflammatory factors deficiency, i.e., defect of IL-13 or IL-23, cause adverse remodeling after MI and can worsen outcomes after AMI [13,14].…”