CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction

Abstract

The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.

Innate Immune Cells in Pressure Overload-Induced Cardiac Hypertrophy and Remodeling

“…Bromodeoxyuridine (BrdU) FACS analysis showed that the proliferation of cardiac resident macrophages peaked at 3 days after TAC injury, whereas the proliferation of total macrophages peaked at 7 days after TAC surgery (Figure 1B, bottom panel) (Liao et al, 2018). In blood, both Ly6C high and Ly6C low monocytes peaked at 7 days after TAC surgery and then went back to the baseline in 3 to 4 weeks (Figure 1C, upper and bottom panels) (Weisheit et al, 2014(Weisheit et al, , 2021Patel et al, 2017). Yet, limited information is available from many other innate immune cells regarding their cardiac infiltration.…”

“…A series of studies illustrated that SAC surgery in rats induced myocardium macrophage infiltration and fibroblast activation at the early phase of hypertrophy (Kuwahara et al, 2003(Kuwahara et al, , 2004. TAC-induced cardiac hypertrophy exhibited expansion of circulating Ly6C high and Ly6C low monocytes and pro-inflammatory CD206 − cardiac macrophages at 1 week after surgery, prior to significant cardiac hypertrophy and dysfunction (Weisheit et al, 2014(Weisheit et al, , 2021Nemska et al, 2016;Patel et al, 2017Patel et al, , 2018Liao et al, 2018; Figure 1B). Recent studies showed that peripheral monocytes from hypertension patients with or without LV hypertrophy also underwent phenotypic alterations.…”

“…A separate study showed slightly different results. Ly6C low macrophages in heart or LV tissues peaked at 7 days after TAC injury, but Ly6C high macrophages in LV tissues peaked at 3 days after TAC injury (Weisheit et al, 2014(Weisheit et al, , 2021Figure 1B, upper panel). Bromodeoxyuridine (BrdU) FACS analysis showed that the proliferation of cardiac resident macrophages peaked at 3 days after TAC injury, whereas the proliferation of total macrophages peaked at 7 days after TAC surgery (Figure 1B, bottom panel) (Liao et al, 2018).…”

“…In contrast, during the perturbed state caused by hemodynamic stress, such as pressure overload and even ischemic injuries, the majority of macrophages are recruited and differentiated from blood monocytes (Molawi et al, 2014). Reacting to the marked upregulation of chemokines, mainly CCL2, CCL7, CCL12, and monocyte-chemoattractant protein (MCP-1) (Dewald et al, 2005;Hashimoto et al, 2013;Hilgendorf et al, 2014;Patel et al, 2018) and chemokine receptors CCR1, CCR2, CCR5, and C-X3-C motif chemokine receptor-1 (CX3CR1) (Weisheit et al, 2014(Weisheit et al, , 2021Nemska et al, 2016), Ly6C high CCR2 high and Ly6C low CX3CR1 high monocytes and macrophages infiltrate into hypertrophic hearts using CCR2 and CX3CR1 within the first week after pressure overload injury (Weisheit et al, 2014(Weisheit et al, , 2021Nemska et al, 2016;Patel et al, 2017Patel et al, , 2018Liao et al, 2018; Figure 3).…”

“…Targeting monocyte/macrophage infiltration has also been proven effective to mitigate cardiac damage after pressure overload-induced hypertrophy. In chemokine Fraktalkine receptor CX3CR1-deficient Cx3cr1 GFP/GFP mice, TACinduced reductions in EF and cardiac output were fully recovered, along with reduced HW/BW, cardiac damage marker aldolase, cardiac hypertrophy and its marker B-type naturetic peptide (BNP), and cardiac fibrosis (Weisheit et al, 2021). Deficiency of CCR2 blocked cardiac tissue macrophage infiltration, increased myocardium capillary density, and improved cardiac function, although it did not affect cardiac tissue fibrosis and cardiomyocyte hypertrophy (Liao et al, 2018).…”