Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation

Abstract

Rationale: TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling. Objective: To investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function. Methods and Results: TGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell–specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments. Conclusions: We demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the infarcted heart from adverse remodeling.

Transforming growth factor–β in tissue fibrosis

“…Thus, TGF-β may promote fibrosis simply by increasing the density of macrophages in injured tissues. Second, TGF-β may enhance expression of profibrotic cytokines by activated macrophages, thus indirectly stimulating tissue fibroblast activation (Chu et al, 2013;Chen et al, 2019). Whether TGF-β targets a specific subset of "fibrogenic" macrophages with distinct functional properties and trafficking patterns remains unknown.…”

Wenxin Granules Influence the TGFβ-P38/JNK MAPK Signaling Pathway and Attenuate the Collagen Deposition in the Left Ventricle of Myocardial Infarction Rats

“…In the transitional state from the inflammatory stage to the repair stage after the occurrence of MI, infiltrating inflammatory cells and matrix binding substances in ECM activate TGFβ and other factors, trigger intracellular related effects and downstream signaling cascade, and play an important role in regulating the inflammation and wound healing as well as tissue remodeling [19]. Under the stimulation of inflammation after MI, the pathological changes of ECM are characterized by excessive accumulation of major components and the transition to repair fibrosis, which means collagen deposition scar instead of injured myocardium [20].…”

Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration

“…Extensive research has been performed to study the importance of growth factors, cytokines, and different components of ECM in the treatment of MI [ 43 , 44 ]. It was shown that transforming growth factor-β (TGF-β) stimulates both Smad3-dependent and independent activation of macrophages, with the involvement of Smad3 in phagocytosis activation, secretion of vascular endothelial growth factor (VEGF) and TGF-β1, and protection against adverse cardiac tissue remodeling [ 45 ]. IL-10 is also important because its deficiency increases necrosis and neutrophil migration, with an enlargement in infarct size.…”