Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models

Abstract

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.

Keywords: animal models; heart failure; inflammation; pressure overload.

Figure 1

Key differences between the ischemic and PO-HF murine model. (1) Type of insult, (2) First to arrive: type of cellular infiltrate, and (3) type of fibrosis. Mon Ly6C^hi: inflammatory monocytes; PMN: Polymorphonuclear neutrophils; PO: Pressure overload.

Figure 2

Graphical representation of changes through time in PO-HF. This figure is divided vertically in four panels (A to D) representing different groups of parameters evaluated; each panel has at its right end, the color code that represents each color line; and along the X-axis at the bottom, a timeline can be observed representing critical time frames for the PO-HF model. The graphical values plotted represent significant changes for increased or decreased values compared with their respective control group at the same moment of measurement. (A) Hemodynamic parameters. (B) Peripheral cell populations. (C) Heart tissue measurements. (D) Thickness of LV wall and dimensions of LV chamber. X-axis represents time. Y-axis is divided into a different set of measured parameters. Values represent significant changes for increased or decreased values compared with control groups. MLN: Mediastinal lymph nodes; EDV: End diastolic volume; LVEF: Left ventricle ejection fraction; Mon: Monocytes; M: Macrophages; M1: Pro-inflammatory macrophages; M2: Anti-inflammatory macrophages; DCs: Classical dendritic cells; BNP: Brain natriuretic peptide.

Figure 3

Summary of the PO-HF murine model. 1) Progressive PO stimulates the release of ATII. ATII stimulates mobilization of Ly6C_hi monocytes from the bone marrow and spleen [30,38,40,41]. ATII and mechanical stress stimulate the expression of chemokines promoting infiltration of Ly6C^hi Mon following its differentiation into M1 [37,56]. 2) Pro-inflammatory cytokines expressed in the heart (e.g., TNFα) as well as released from M1 and chemokines further stimulates mobilization and infiltration of CD4⁺ T cells [38,40,47,48]. M1 produce IL-12, which induces IFN-ɣ by T cells that activate macrophages that produce MCP1, creating a positive feedback of monocyte infiltration, M1 activation, and T cell infiltration and activation [54]. 3) Mechanical stress induces expression of structural genes that lead to a hypertrophic response. 4) ATII stimulates M2 production of TGFβ, leading to fibroblast stimulation and a reactive fibrotic response [37,39,57]. However, it is still not clear the process of transition from M1 to M2 [58]. Then, macrophage population starts to decline progressively, which correlates with a reduced number of circulating monocytes [47,48], marking the beginning of the transition from an innate to an adaptive response. 5) Expansion of T cells in the heart and expression of leukocyte adhesion molecules, VCAM1, E-Sel, and ICAM1 [47]. Increased IL-4 and BAFF suggests the participation of B cells, key modulators of the T cell response [49,50,51]. Structurally it starts a progressive increase of EDV [48,50]. 6) The second peak of DCs is observed and the predominance of the CD4⁺ T cell subset and deposition of IgG3 suggests that the sustained inflammatory response belongs to the adaptive immune response with both cellular and humoral participation [49,50].