Abstract
Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.
Highlights
This review will focus on the leukocyte dependent regulation of fibrosis since it has been well reported that the activation of resident fibroblasts into myofibroblasts is heavily influenced by changes in the myocardial environment (Davis and Molkentin, 2014; Stempien-Otero et al, 2016)
5 day post myocardial infarction (MI), increase in CD206 and or Arg-1 expressing neutrophils is associated with decreased myofibroblast transdifferentiation (Kain et al, 2018) 7 days post MI, neutrophils express Fibronectin, Gal-3, Fibrinogen which contributes to extracellular matrix (ECM) reorganization (Daseke et al, 2019) 21 days post MI, loss of MPO reduces fibrosis (Mollenhauer et al, 2017) Post MI, loss of neutrophil gelatinaseassociated lipocalin (NGAL) expressing neutrophils may affect dead myocyte phagocytosis and contribute to fibrosis (Horckmans et al, 2017)
Fibrotic remodeling is a normal physiological response to injury in the heart, when it becomes excessive, fibrosis leaves the heart at a great detriment in that it leads to tissue stiffness and dysfunction (Hinderer and Schenke-Layland, 2019)
Summary
The healthy heart is supported by a distinct network of extracellular matrix (ECM) proteins, which function in part to preserve chamber structure and aid in cardiac cell communication (Lu et al, 2011; Frangogiannis, 2017). This review will focus on the leukocyte dependent regulation of fibrosis since it has been well reported that the activation of resident fibroblasts into myofibroblasts is heavily influenced by changes in the myocardial environment (Davis and Molkentin, 2014; Stempien-Otero et al, 2016) This is important to note, as injury results in damaged cardiomyocytes which incite inflammation and promote a large expansion and infiltration of leukocytes (Swirski and Nahrendorf, 2013; Grisanti et al, 2016a,b; Swirski and Nahrendorf, 2018). We will examine the current understanding of leukocytes in cardiac biology, focusing on how they may regulate cardiac fibrosis, and examining if they can be targeted to control fibrosis
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