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Review
. 2020 Sep 28;21(19):7165.
doi: 10.3390/ijms21197165.

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

Denisa Baci  1 , Annalisa Bosi  2 , Luca Parisi  3 , Giuseppe Buono  4 , Lorenzo Mortara  1 , Giuseppe Ambrosio  5 , Antonino Bruno  4
Affiliations
Review

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

Denisa Baci et al. Int J Mol Sci. .

Abstract

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in "sterile" inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.

Keywords: cardiac fibrosis; eosinophils; inflammation; macrophages; mast cells; natural killer cells; neutrophils.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neutrophils in cardiac fibrosis. (A) Neutrophils massively infiltrate the infarcted area in the first few hours being the earliest detectable immune population following ischemia onset. (B) Neutrophils can release large amount of pro-fibrotic agents, such as Interleukin-1 (IL-1)β, NOX4, and metalloproteinases (MMPs), which, along with the generation of ROS, instruct cardiac fibroblasts to produce collagen and support collagen deposition, in an Akt/mTOR, NFκB-dependent manner. (C) N2-like neutrophils accumulate in the infarcted area and release TGF-β, thus favouring collagen production and deposition by cardiac fibroblasts. (D) Injured cardiomyocytes are able to activate pro-fibrotic/pro inflammatory/TGF-β producing myofibroblasts, using IL-1β, S100A8, and S100a9 producing neutrophils, as bystander cells. (E) Neutrophils can also impact MI and fibrosis by releasing extracellular traps (NETs). NETs promote the recruitment and activation of platelets that are a relevant source of TGF-β, thus indirectly supporting fibrosis. (F) Apoptotic neutrophil elimination by macrophages represent a crucial anti-inflammatory and pro-resolving signal itself. Apoptotic neutrophils induce anti-inflammatory mediators, including TGF-β, IL-10, and resolvins, which are pivotal in driving pro-resolving microenvironment.
Figure 2
Figure 2
Macrophages in cardiac fibrosis. (A) During the first phase of tissue inflammation, macrophages acquire a “classically activated” (M1-like) state. In the later phase, macrophages switch into a reparative phenotype, producing anti-inflammatory cytokines, chemokines, and growth factors such as IL-10, TGF-β, VEGF, angiotensin II, bFGF, and PDGF [114,115]. The transition to this reparative state seems to be induced via nuclear receptor subfamily 4 group A member 1 (NR4A1). M2-like macrophages also produce the pro-fibrotic agent TGF-β that induce collagen secreting and collagen stabilizing myofibroblasts. High numbers of macrophages accumulate in the damaged heart, localizing in proximity to myofibroblasts, that, by producing TGF-β, angiotensin II, PDGF, TNFα, and IL-1β, stimulate induce the differentiation of cardiac fibroblasts into myofibroblasts in an autocrine manner. (B) Some of the cardiac infiltrating fibroblast can originate from a circulating monocytic CD14+ cell subset, termed fibrocytes. Under profibrotic stimulation, these cells have been shown to increase the expression of ECM components, such as collagen and fibronectin, and of the mature myofibroblast marker α-SMA. Increased number of circulating fibrocyte has been observed during cardiac fibrosis, in response to the augmented circulating levels of MCP-1/CCL2, CCL4, and CCL3. (C) Neoregulin-1 (NRG-1) can exert antifibrotic and anti-inflammatory effects acting on macrophages in an ErbB4-mediated manner. After fibrotic stimuli, NRG-1, released from damaged endothelial cells in the endocardium, activates ErB4 and downregulates the PI3K/Akt pathway and the phosphorylation of STAT3 thus reducing the release of proinflammatory mediators such as IL-1β, iNOS, IL-6, and TNF-α. The activation of ErbB4 results in the reduction of new monocytes recruitment and suppression of the inflammatory state. (D) Ly6Chigh macrophages infiltrate in hypoxic areas in a hypoxia-inducible factor (HIF-1α)-dependent manner and inhibits TGF-β cardiac fibroblast activation by the release of oncostatin M (OSM).
Figure 3
Figure 3
Natural killer (NK) cells in cardiac fibrosis. (A) Activated NK cells have been found to accumulate in the heart and release granzyme-B and IFN-γ, along with enhanced expression of CD69, TRAIL, and CD27 activation markers. This NK cell hyperactivation result in decreased cardiac fibrosis by inhibiting eosinophil activation and inducing eosinophil apoptosis, within an anti-inflammatory microenvironment. (B) Following myocardial infarction, expansion of NK cells from c-Kit+ bone marrow cells have been reported to protect the heart by reducing cardiomyocyte apoptosis [186], deposition of collagen and subsequent fibrosis, and by promoting neovascularization.
Figure 4
Figure 4
Eosinophils (EOs) in cardiac fibrosis. (A) Increased infiltrations of EOs, overexpressing chemokines and cytokines involved in innate and adaptive immunity, such as IL-4, eotaxin, and RANTES has been reported to support fibrosis, by activating cardiac fibroblasts to release and deposit collagen. (B) Depletion of NK cells generated a pro-eosinophilic environment, as showed by the high increase of cardiac-infiltrating EOs in vivo that was correlated with increased fibrosis.
Figure 5
Figure 5
Mast cells (MCs) in cardiac fibrosis. (A) Accumulation of MCs in cardiac tissues has been observed in several cardiovascular diseases (CVDs). (B) MCs secrete several pro-fibrogenic factors such as bFGF, chymase and tryptase that have been long linked with cardiac fibrosis since can trigger fibroblasts activation directly or by promoting AngII, and TGF-β1. MCs degranulation- derived inflammatory cytokines, including TNF-α, IL-1β, can also drive fibrotic remodeling of the heart, via TGF-β-producing fibroblasts and by enhancing collagen production and deposition in cardiac fibroblasts. (C) MCs also act as anti-fibrotic mediators and anti-inflammatory cytokines/chemokines. MCs can produce IL-10, IL-13, and IL-33, known as potent inhibitors of the fibrotic signaling by blocking bone marrow fibroblast precursor cell migration in the heart and their differentiation towards myofibroblasts, triggering cardiac tissue resident macrophage to display M2 anti-fibrotic phenotype and attenuating tissue-remodeling and reduces fibrosis after cardiac injury, respectively. Finally, vascular endothelial growth factor (VEGF)-producing MCs promote re-capillarization of the cardiac tissue and reduce fibrosis.
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