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    • br Macrophage roles in cardiac injury responses While cTMs m

    2018-11-06


    Macrophage roles in cardiac injury responses While cTMs may play an important role in cardiac homeostasis, they are likely to be amongst the first cell types to react to cardiac tissue damage. Following injury, a robust inflammatory response involves secretion of various cytokines and infiltration and mobilisation of multiple cell types. Inflammation recruits exogenous monocytes/macrophages that have diverse functions (Fig. 4), distinct developmental origins and bear a different phenotype to cTMs, and the ways in which cTMs and invading monocytes/macrophages interact to progress the wound healing response and influence each other\'s phenotype are yet to be identified. A major factor initiating the injury response cascade is the necrosis-dependent release of intracellular contents and cellular debris, which is recognised by various cox 2 inhibitors presenting PRRs, including cTMs (Pinto et al., 2012). These factors are likely to override any intrinsic immune-dampening elements and signal entry of neutrophils, the first exogenous myeloid cells that peak in number within 24h after injury. Neutrophils phagocytose tissue debris and degranulate to release inflammatory mediators before submitting to phagocytosis by macrophages. Monocytes next enter the lesion by homing to soluble chemotactic cues such as MCP-1 and Cx3cl1, and differentiate to macrophages (Nahrendorf et al., 2007; Nahrendorf & Swirski, 2013). MCP-1 is a key monocyte/macrophage chemoattractant and is produced by a range of cardiac cells, including endothelial cells, macrophages and fibroblasts, within hours following cardiac injury (Dewald et al., 2005). Ablation of the Mcp-1 receptor Ccr2 results in the severe impairment of the monocyte influx into damaged tissue (Majmudar et al., 2013; Kaikita et al., 2004). After cardiac injury, two classes of macrophage are sequentially predominant within damaged myocardium: the classically activated ‘M1’, and alternatively activated ‘M2’ macrophages. The M1 and M2 paradigm, while an oversimplification, describes two broad and heterogeneous macrophage classes at the extremes of a continuum of maturation states (Mosser & Edwards, 2008). Extensive research has established this model in wound healing and inflammation in many tissues (Jenkins et al., 2011; Nahrendorf et al., 2007; Arnold et al., 2007). Instrumental for the study of M1 and M2 macrophages, particularly in the mouse, has been the identification of cell surface markers that have enabled their discrimination, such as Ly6C (where M1 and M2 are Ly6Chigh and Ly6Clow, respectively), Mrc1 (also known as CD206; where M1 and M2 macrophages are Mrc1− and Mrc1+, respectively) and Cx3cr1 (where M1 and M2 macrophages are Cx3cr1low and Cx3cr1high, respectively) (Nahrendorf et al., 2007; Arnold et al., 2007). Within the first 5days (the wound healing phase) and peaking at approximately 3days after cardiac injury, the M1 macrophage subtype predominates, characterised by their fibrolytic, phagocytic and inflammatory properties, releasing inflammatory mediators such as TNFα, IL-6, IL-1β, Ccl2, Ccl5 and nitric oxide (NO) (Nahrendorf et al., 2007; Murray & Wynn, 2011). M1 macrophages undertake extensive phagocytic activity to clear necrotic and apoptotic debris including remnant neutrophils, and release fibrolytic proteases such a MMP-1, -2, -7, -9 and -12 which facilitates cells to penetrate towards the injury lesion, paving the way for tissue granulation. Following the infiltration of M1 macrophages, approximately 7days post-MI the injury-resolution phase begins with M2 macrophages becoming predominant (Nahrendorf et al., 2007). M2 macrophages are characterised as anti-inflammatory, salutary, and fibrogenic (Murray & Wynn, 2011). Anti-inflammatory factors including IL-10, IGF-1 and lipid mediators such as lipoxins, resolvins and protectins (discussed above) drive resolution of the acute inflammatory response. M2 macrophage-derived factors, such as FGF2, IGF-1, PDGF, TGFβ1 and VEGF are angiogenic, limiting cell death due to lack of blood supply (Nakao-Hayashi et al., 1992; Nahrendorf et al., 2007; Grant et al., 1993b; Roberts et al., 1986). Angiogenesis is also supported by M2 macrophage production of ECM modulating factors such as matrix metallopeptidases (MMPs) (Zijlstra et al., 2004) and serine proteases (u-PA, t-PA) that liberate ECM-bound growth factors and regulate both angiogenesis and mobilisation of other cell types (Eming & Hubbell, 2011).