Heart Inflammation: Immune Cell Roles and Roads to the Heart

Abstract

Heart failure (HF) has been traditionally viewed as a disease of the cardiac muscle associated with systemic inflammation. Burgeoning evidence implicates immune effector mechanisms that include immune cell activation and trafficking to the heart. Immune cell infiltration in the myocardium can have adverse effects in the heart and contribute to the pathogenesis of HF. Both innate and adaptive immunity operate sequentially, and the specificity of these responses depends on the initial trigger sensed by the heart. Although the role of the immune system in the initial inflammatory response to infection and injury is well studied, what sets the trajectory to HF from different etiologies and the role of immunity once HF has been established is less understood. Herein, we review experimental and clinical knowledge of cardiac inflammation induced by different triggers that often result in HF from different etiologies. We focus on the mechanisms of immune cell activation systemically and on the pathways immune cells use to traffic to the heart.

Figure 1

Immune cell development and trafficking to the heart. Lymphoid progenitors traffic to the thymus, where they undergo positive and negative selection on recognition of new antigens or self-antigens, respectively. Positively selected T-cell clones migrate to the secondary lymphoid organs [lymph nodes (LNs) and spleen] and wait for antigen presentation by dendritic cells (DCs) to induce specific T-cell responses and acquisition of migratory phenotypes that will guide them to the heart. Myeloid progenitors traffic to secondary lymphoid organs. Heart inflammation results in endothelial adhesion molecules in the intramyocardial vessels that mediate T-cell and myeloid extravasation. Data from ischemic (solid lines) and nonischemic (dotted lines) models of experimental heart failure (HF) suggest that neutrophils (1) and monocytes (2) will be recruited from the bone marrow and the spleen by the CCR2/chemokine (C-C motif) ligand (CCL) 2–CCL5 pathway and contribute to heart inflammation in response to ischemia and pressure overload T cell (3) traffic from lymph nodes and use CXC chemokine receptor 3 (CXCR3) and the lymphocyte function–associated antigen 1 (LFA-1)/intercellular adhesion molecule 1 (ICAM-1) to infiltrate the heart in nonischemic HF. T-cell expansion occurs in the spleen and LNs in response to ischemia, and LFA-1 and very late antigen 4 (VLA-4) mediate heart infiltration. CXCL, C-X-C motif ligand; IFN, interferon; MHC, major histocompatibility complex; PD-1, programmed cell death-1; PDL-1, PD-1 ligand; TCR, T-cell receptor; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

Distinct triggers of cardiac inflammation and progression of adverse cardiac remodeling and chronic inflammation in heart failure (HF) from different etiologies. A: Viral, bacterial, or parasite infection of the myocardium/endocardium leads to cell death and triggers a highly proinflammatory response to induce pathogen killing. Many monocytes/macrophages, neutrophils, and T cells infiltrate the heart during the acute phase of infection through different adhesion molecules. The payback of pathogen killing is off-target effects of inflammation in the myocardium and tissue fibrosis, which develop into chronic inflammation and cardiac hypertrophy. Pathogen titers are low inexistent in the chronic inflammatory phase dominated by heart-infiltrated macrophages and T cells, which contribute to cardiac fibrosis and remodeling. B: Myocardial ischemia induces cardiomyocyte death and recruitment of many neutrophils (first) and sequential waves of monocytes (second) and T cells (third) to promote healing and scar formation by inducing fibrosis in the infarct zone (acute inflammation). Acute strong inflammation and scar formation lead to more fibrosis to maintain the tissue integrity filling in areas of cardiomyocyte death, and expanded fibrosis [by transforming growth factor-β (TGF-β) production], cardiac hypertrophy, but lower numbers of immune cells that include T-helper type 2 and T-helper type 17 (Th17) cells are found in the heart in chronic inflammation after ischemia. C: Hypertension and pressure overload, unlike infection or ischemia, are not characterized by extensive inflammation in the acute phase. Monocytes and T-helper type 1 (Th1) cells progressively infiltrate the heart in low numbers as cardiac fibrosis and cardiac hypertrophy develop, initially in response to cardiac pressure overload, and later resulting in dilated cardiomyopathy, cardiac dysfunction, and HF. D: Several other factors, which include diabetes, chemotherapy, and genetic mutations, can induce adverse cardiac remodeling and progress into HF, but the role of inflammation is largely unexplored. CaMKIIδ, calmodulin kinase II delta; CCL, chemokine (C-C motif) ligand; CCR, C-C motif receptor; CXCL, C-X-C motif ligand; CXCR, C-X-C motif receptor; DAMP, damage-associated molecular pattern; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; LFA-1, lymphocyte function-associated antigen 1; LPS, lipopolysaccharide; LV, left ventricular; MMP, matrix metalloprotease; T. cruzi, Trypanosoma cruzi; TNF-α, tumor necrosis factor-α; Treg, T regulatory; VCAM-1, vascular cell adhesion molecule 1.