Induction of the CXC Chemokine Interferon-γ-Inducible Protein 10 Regulates the Reparative Response Following Myocardial Infarction

Abstract

Key Words: infarction Ⅲ remodeling Ⅲ chemokines Ⅲ fibrosis Ⅲ wound healing M yocardial infarct healing is dependent on activation of an inflammatory cascade, followed by granulation tissue formation and deposition of collagen-based matrix. 1,2 Rapid induction of inflammatory chemokines, cytokines and adhesion molecules in the infarcted myocardium results in chemotactic recruitment of leukocytes. Neutrophils and activated macrophages clear the wound from dead cells and debris while secreting mediators that promote fibroblast growth and angiogenesis. The intense, but transient, inflammatory response is followed by repression of cytokine synthesis and activation of fibrogenic and angiogenic pathways. Activated myofibroblasts produce extracellular matrix proteins, whereas neovessels provide oxygen and nutrients necessary for the metabolically active wound. As the infarct matures, fibroblasts and vascular cells undergo apoptosis and a hypocellular collagenous scar is formed. Optimal repair of the infarcted myocardium is dependent on timely induction and suppression of inflammatory pathways and on endogenous mechanisms that ensure containment of the fibrotic response within the area of the infarct. Disturbances in the mechanisms involved in regulation of the reparative process result in formation of a defective scar with altered mechanical properties, leading to increased adverse remodeling.The chemokines are inflammatory mediators with an essential role in leukocyte trafficking. Several members of the chemokine family are markedly and consistently induced in healing infarcts, modulating the postinfarction inflammatory response through recruitment of leukocyte subpopulations. 3,4,5,6,7 The CC chemokine monocyte chemoattractant protein-1/CCL2 plays a crucial role in chemotaxis and acti-

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

“…Interestingly, several studies have demonstrated an important role for IFN signaling in the activation and recruitment of Tregs to injured tissue (45,46,59,60). IFN-γ has been shown in prior studies to affect multiple pathways, including suppression of fibrosis in chronic myocarditis by reducing profibrotic cytokine secretion (61), as well as mediation of basic FGF-induced (bFGF-induced) fibroblast migration via CXCL10 (62). Recently, however, Tregs have been shown to express the IFN-γ-specific receptors IFN-γR1 and IFN-γR2, thereby allowing a subset of these cells to be mediated directly by the chemokine IFN-γ (45).…”

Absence of Chemokine (C-X-C Motif) Ligand 10 Diminishes Perfusion Recovery After Local Arterial Occlusion in Mice

“…CXCL10 has been described previously as a potent chemokine for attracting inflammatory cells, especially monocytes and T lymphocytes 12,22 but has also been associated with angiogenesis in the ischemic myocardium after induction of MI in mice. 21 In this study, we investigated the causal role of CXCL10 for perfusion recovery in a mouse model for hindlimb ischemia.…”

Systematic Characterization of Myocardial Inflammation, Repair, and Remodeling in a Mouse Model of Reperfused Myocardial Infarction

“…Left ventricular (LV) dimensions were measured in parasternal long-axis view using 2D-directed M-mode echocardiography as previously described (Bujak et al 2009). The following parameters were measured as indicators of LV function and remodeling: LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and fractional shortening (FS = 100 × [LVEDD -LVESD]/ LVEDD).…”