Sca‐1⁺ cardiac fibroblasts promote development of heart failure

Abstract

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45 CD31 CD29 mEF-SK4 PDGFRα Sca-1 periostin (Sca-1 ) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1 periostin cardiac fibroblasts (Postn Il17ra ) protected mice from post-infarct heart failure and death. Moreover, Postn Il17ra mice had significantly fewer GM-CSF-producing Sca-1 cardiac fibroblasts and inflammatory Ly6C monocytes in the heart. Sca-1 cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1 cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches

“…GM-CSF has been shown to be upregulated either systemically and/or in the diseased tissues of patients with autoimmune conditions (such as rheumatoid arthritis) 2,26 as well as in conditions that show similarities to late-stage COVID-19, including severe acute respiratory syndrome (SARS) 27 , acute respiratory distress syndrome (ARDS) 28 , cytokine release syndrome (CRS) 29 , haemophagocytic lymphohistiocytosis (HLH) 30 , hyperinflammation associated with graft-versus-host disease (GvHD) 31 and other inflammatory diseases of the lung 32 , heart [33][34][35] and nervous system 21,23,36,37 . GM-CSF-producing T H cells have been identified as being involved in the pathogenesis of various immunological disorders (for example, rheumatoid arthritis 26 , multiple sclerosis 21,22 and sepsis 38 ), reminiscent of the pathogenic T H 17 pathway known to drive disease pathology in multiple autoimmune contexts (for example, psoriasis) 39 .…”

Origin and functional heterogeneity of fibroblasts

“…For example, periostin-expressing cardiac fibroblasts, genetically modified to lose IL-17RA and therefore IL-17 signaling, reduce their production of the pro-fibrotic growth factor GM-CSF (granulocyte-macrophage colony stimulating factor), effectively limiting cardiac inflammation and tissue death. 161 The secretome of fibroblasts in cardiac fibrosis thus appears to be reciprocally regulated by immune cell secretomes. Similarly, in wounded skin, the cross-talk between macrophage and adipocyte precursors determines the heterogeneous composition myofibroblasts in the wound with impact on skin regeneration and scarring.…”

<p>GM-CSF: A Promising Target in Inflammation and Autoimmunity</p>

“… 50 GM-CSF has been reported to be expressed by cardiac fibroblasts in models of Kawasaki disease and myocarditis. 51 , 52 Epithelial cells can produce GM-CSF in response to allergenic stimuli 53 , 54 and such production can restore alveolar barrier function. 55 In addition, studies also reported that endothelial cells can produce GM-CSF in response to pro-inflammatory cytokine stimulation.…”