Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Abstract

Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress

“…In addition to Ca 2+ dyshomeostasis, TNF-α also causes direct cytotoxicity [35], oxidative stress [36], disruption of excitation-contraction coupling [37], up-regulation of other cardiac suppressing cytokines (e.g., IL-1β) [38,39] and induction of cardiomyocyte apoptosis [40], all of which impair cardiac contractile function in cardiomyocytes, isolated hearts and intact animals. Pro-inflammatory response may also promote fibrosis in heart [41,42]. Having shown that disruption of calpain inhibited ER stress, we further demonstrated that deletion of capns1 prevented pro-inflammatory cytokines expression in HFD-fed mouse hearts and silencing of capn1 inhibited palmitate-induced pro-inflammatory response in cardiomyocytes.…”

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

“…In contrast, FN circulates in the soluble form in plasma or accumulates in tissue as insoluble ECM components (32). There is a marked upregulation of FN in the plasma during inflammatory conditions (33,34), and there is extravasation of this plasmatic protein in the basement membrane of the inflamed tissue (35). Moreover, FN has the ability to act as an endogenous ligand for TLR4 and to activate its signaling pathway, which leads FN-PMN).…”

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

“…Fibroblasts are abundant in the heart and have multiple potential roles during myocardial inflammation and repair that follows MI (Porter & Turner 2009). In addition to the production of collagen and other matrix proteins that determine scar integrity, they secrete molecules, including cyto­kines, prostaglandins (Shinde & Frangogiannis 2014, Fernando et al 2015, Turner 2016) and microRNA (Fang & Yeh 2015), capable of regulating inflammation (Porter & Turner 2009, Chen & Frangogiannis 2013, van Nieuwenhoven & Turner 2013), Treg recruitment (Frangogiannis 2014), angiogenesis (Newman et al 2011), cardiogenesis (Furtado et al 2014) and hypertrophy (Abonnenc et al 2013, Cartledge et al 2015). The role of cardiac fibroblast 11β-HSD1 in regulating the cellular secretome and on the response to MI and other pathological challenges merits further investigation.…”