Lymphocytic subsets play distinct roles in heart diseases

Abstract

Heart diseases are one of the leading causes of death for humans in the world. Increasing evidence has shown that myocardial injury induced innate and adaptive immune responses upon early cellular damage but also during chronic phases post-injury. The immune cells can not only aggravate the injury but also play an essential role in the induction of wound healing responses, which means they play a complex role throughout the acute inflammatory response and reparative response after cardiac injury. This review will summarize the current experimental and clinical evidence of lymphocytes, one of the major types of immune cells, participate in heart diseases and try to explain the possible role of these immune cells following cardiac injury.

Leukocyte-Dependent Regulation of Cardiac Fibrosis

“…Beyond these findings, however, it is also important to note the wealth of literature that hints at an opposing role for DCs following injury. With CD11c + cell depletion, 24 weeks after TAC, mice exhibit reduced LV fibrosis and decreased expression of fibroblast activating genes (Wang et al, 2017). These studies are met with similar critiques regarding lack of DC specificity, however, studies using a more specific model of cDC ablation also show decreased LV fibrosis 3 weeks post-MI (Lee et al, 2018).…”

“…Pathological context Contribution to fibrosis Neutrophils Ischemia 5 day post 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 ECM reorganization (Daseke et al, 2019) 21 days post MI, loss of MPO reduces fibrosis (Mollenhauer et al, 2017) Post MI, loss of NGAL expressing neutrophils may affect dead myocyte phagocytosis and contribute to fibrosis (Horckmans et al, 2017) Myocarditis/DCM; Ageing In chronic myocarditis and ageing decreased neutrophil infiltration and NETosis/NET formation is associated with reduced fibrosis (Martinod et al, 2017;Weckbach et al, 2019) Monocytes/Macrophages Ischemia 1-6 weeks post MI, macrophages may transition to fibroblast-like cells, capable of secreting collagen (Haider et al, 2019) IL-10 and TGFβ secreting macrophages promote myofibroblasts transdifferentiation (O'Rourke et al, 2019) 1 week post ischemia/reperfusion, loss of MCP-1 is associated with decreased macrophage infiltration and interstitial fibrosis (Frangogiannis et al, 2007) 4 weeks post MI, Gata6 expressing pericardial macrophages limit cardiac fibrosis (Deniset et al, 2019) Pressure Overload Macrophage associated Gal-3 correlates with increased cardiac fibrosis in hypertensive rats (de Boer et al, 2009) 8 weeks following uninephrectomy and salty drinking water, loss of macrophage expressed mineralocorticoid receptor reduces cardiac collagen content (Rickard et al, 2009) Mast Cells Pressure Overload Mast cells contribute to PDGF-A expression and fibrosis in the heart following TAC (Liao et al, 2010) DCM Mast cells are a large source of FGF-2, and found within fibrotic sections of cardiac tissue (Bradding and Pejler, 2018) Eosinophils Myocarditis/DCM Eosinophil depletion post myocarditis is associated with decreased levels of MMP-2 and TIMP-2 (Diny et al, 2017) Dendritic Cells Ischemia Ablation of dendritic cells results in increased MMP-9 and MMP-2 activity 3-28 days post MI (Anzai et al, 2012) Pressure Overload Dendritic cell ablation following TAC is associated with decreased IL-1β and TGFβ and less fibrosis (Wang et al, 2017) Myocarditis/DCM BATF3 dependent dendritic cells limit cardiac fibrosis following viral infection (Clemente-Casares et al, 2017)…”

“…These cDCs have been shown to mediate tolerance to self-antigens (Van der Borght et al, 2017). DCs become of even greater relevance as the heart experiences injury (Clemente-Casares et al, 2017;Van der Borght et al, 2017;Wang et al, 2017). Their specific roles in pathology, especially in relation to cardiac fibrosis, is distinct; we consider them below.…”

“…An abundance of literature suggests an involvement of both B and T-Lymphocytes (B and T cells) in cardiac fibrosis. These adaptive immune cells are found in small numbers in the steady state heart, but are known to rise post-injury (Zouggari et al, 2013;Wang et al, 2019). The functional relevance of these lymphocytes in the steady state heart is still becoming understood, however, following injury, several reports have documented their ability to influence long-term remodeling outcomes (Yu et al, 2013;Zouggari et al, 2013;Horckmans et al, 2018).…”

The Dynamic Interplay Between Cardiac Inflammation and Fibrosis

“…Cytotoxic T cells are activated after infarction and may exert cytotoxic actions on healthy cardiomyocytes in a mechanism that is thought to involve cross-reactive cardiac antigens ( Varda-Bloom et al, 2000 ; Ilatovskaya et al, 2019 ). B cells are also recruited to the heart through poorly understood mechanisms ( Wang et al, 2019 ). They are thought to have a negative impact on remodeling though their role is not well defined ( Adamo et al, 2018 , 2020 ).…”