The role of endogenous Smad7 in regulating macrophage phenotype following myocardial infarction

Abstract

Smad7 restrains TGF‐β responses, and has been suggested to exert both pro‐ and anti‐inflammatory actions that may involve effects on macrophages. Myocardial infarction triggers a macrophage‐driven inflammatory response that not only plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that macrophage Smad7 expression may regulate inflammation and fibrosis in the infarcted heart through suppression of TGF‐β responses, or via TGF‐independent actions. In a mouse model of myocardial infarction, infiltration with Smad7+ macrophages peaked 7 days after coronary occlusion. Myeloid cell‐specific Smad7 loss in mice had no effects on homeostatic functions and did not affect baseline macrophage gene expression. RNA‐seq predicted that Smad7 may promote TREM1‐mediated inflammation in infarct macrophages. However, these alterations in the transcriptional profile of macrophages were associated with a modest and transient reduction in infarct myofibroblast infiltration, and did not affect dysfunction, chamber dilation, scar remodeling, collagen deposition, and macrophage recruitment. In vitro, RNA‐seq and PCR arrays showed that TGF‐β has profound effects on macrophage profile, attenuating pro‐inflammatory cytokine/chemokine expression, modulating synthesis of matrix remodeling genes, inducing genes associated with sphingosine‐1 phosphate activation and integrin signaling, and inhibiting cholesterol biosynthesis genes. However, Smad7 loss did not significantly affect TGF‐β‐mediated macrophage responses, modulating synthesis of only a small fraction of TGF‐β‐induced genes, including Itga5, Olfml3, and Fabp7. Our findings suggest a limited role for macrophage Smad7 in regulation of post‐infarction inflammation and repair, and demonstrate that the anti‐inflammatory effects of TGF‐β in macrophages are not restrained by endogenous Smad7 induction.

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…Two inhibitory smads (smad6 and smad7) can prevent R-smad phosphorylation ( Bertaud et al, 2023 ). Further, smad7 also restrains MFs activation by suppressing profibrotic ERBB2 in a TGF-β-independent manner ( Humeres et al, 2022 ) but does not restrain the anti-inflammatory function of TGF-β in macrophages ( Li et al, 2022d ). Another member of the TGF-β superfamily, lefty1 alleviates post-MI CFs proliferation, differentiation, and secretion by suppressing the p-smad2 and p-ERK1/2 axis ( Li et al, 2021a ).…”

Extracellular Vesicles Containing GAS6 Protect the Liver from Ischemia-Reperfusion Injury by Enhancing Macrophage Efferocytosis via MerTK-ERK-COX2 Signaling

“…Additionally, bridging molecules like growth arrest-speci c 6 (GAS6) or milk fat globule epidermal growth factor-factor VIII facilitate e cient removal of dying cells [9][10] [11]. Recent research has highlighted how GAS6-Mer interaction can offer both anti-in ammatory and pro-survival effects against HIRI [12][13] [14], underscoring the signi cance of targeting phagocytic signaling for mitigating liver injury.…”