CXCL1–CXCR2 lead monocytes to the heart of the matter

This editorial refers to ‘CXCL1–CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration’†, by L. Wang et al., on page 1818. Development of hypertension in humans and in animal models is associated with endothelial dysfunction and vascular remodelling, and stiffening of large and small arteries, leading to stroke, to cardiac hypertrophy, and eventually to heart failure, and to chronic kidney disease. The pathophysiology of hypertension and associated cardiovascular disease is complex. Neuro-humoral factors such as the renin–angiotensin–aldosterone and endothelin systems, the sympathetic nervous system, genetic predisposition, environmental factors such as a high salt intake, and ageing, in combination or independently contribute to elevation of blood pressure (BP), and BP and/or the pro-hypertensive stimuli induce cardiovascular injury. It is now well appreciated that low-grade inflammation plays a role in the development and progression of hypertension and cardiovascular disease.1–4 Adhesion molecules, chemokines and cytokines, and innate (monocytes/macrophages) and adaptive immune cell infiltration (T lymphocytes) are enhanced in cardiovascular tissues in hypertension. Genetic manipulation and adoptive immune cell transfer experiments have demonstrated that deficiency in monocytes/macrophages, T helper (Th) 1, and Th17 lymphocytes counteract BP elevation and vascular injury in hypertensive models. Innate immune cells play a role in the initiation and subsequent direction of the adaptive immune response, key mechanisms in hypertension, and vascular injury. T regulatory lymphocytes (Treg), a subset of T lymphocytes that exert immunosuppressive actions on Th1, Th2, and Th17, are decreased in hypertensive models. We and others have shown using genetic manipulation and adoptive transfer experiments that Treg have the potential to reduce the development of hypertension and vascular or cardiac injury. Recently, we demonstrated using loss-of-function approaches that a small subset of T lymphocytes expressing γδ T cell receptors (TCRs) instead of conventional αβ TCRs, which have innate-like features, are required for angiotensin II-induced BP elevation and endothelial dysfunction, and activation of T effector lymphocytes.5 Thus, most cellular components of the immune system in one way or another modulate cardiovascular injury and BP elevation. Attraction of immune cells to sites of injury in altered cardiovascular tissues is mediated by increased expression of chemokines.6 Immune cells expressing appropriate G protein-coupled chemokine receptors follow the increasing gradient of chemokines to the injury site.7 Forty-five chemokine ligands (L) and 15 chemokine receptors (R) have been identified and are divided into four subgroups based on the spacing of conserved cysteine residues: CC, CXC, C, and CX3C. The chemokine ligand–receptor pairings are complex, as most chemokines bind more than one receptor, and vice versa. The roles of a few chemokine ligands and receptors have been studied in hypertension and associated cardiovascular injury.6 CCL2 [monocyte chemoattractant protein 1 (MCP1)] directs the attraction of neutrophils, monocytes, and T cells to inflammation sites via CCR2. In hypertension, CCL2 and CCR2 expression is increased in cardiovascular cells and in circulating monocytes, respectively.6 Ccr2 knockout experiments have shown that CCR2 plays a role in the development of vascular remodelling and in kidney injury in hypertension, but not in BP elevation.8–10 CCR2 binds not only CCL2 but also CCL7, CCL8, CCL12, and CCL13, whereas CCL7 and CCL13 bind to other chemokine receptors.7 CCL5 [regulated on activation, normal T cell expressed and secreted (RANTES)] attracts monocytes and T cells to inflammatory sites. Mikolajczyk et al.11 showed that angiotensin II-induced hypertension was associated with increased expression of CCL5 and infiltration in perivascular adipose tissue of T cells expressing the CCL5 receptors CCR1, CCR3, and CCR5. Ccl5 knockout reduced angiotensin II-induced endothelial dysfunction, vascular oxidative stress, and perivascular infiltration of interferon γ-expressing CD8+ and CD3+CD4–CD8– T cells without altering BP elevation. Recently, Wang et al. demonstrated an important role for the CXCL1–CXCR2 axis in hypertension and vascular injury.12 They observed in microarrays that in mouse aorta Cxcl1 was the most highly expressed chemokine compared with 12 other chemokines after 1 day of angiotensin II infusion. Cxcr2 expression in the aorta was increased in angiotensin II-infused mice, together with infiltration of leucocytes expressing the CXCL1 receptor CXCR2. Cxcr2 knockout, or selective CXCR2 antagonism with SB265610, blunted angiotensin II-induced BP elevation, aortic endothelial dysfunction and vascular remodelling, fibrosis, oxidative stress, inflammation, and macrophage and T cell infiltration. Cxcr2 knockout was also effective in preventing DOCA (desoxycorticosterone acetate)/salt hypertension and vascular injury. Bone marrow transplantation studies demonstrated that it is CXCR2 expressed on immune cells that plays a role in hypertension and vascular injury. This may be relevant to humans as the number of CXCR2-expressing monocytes, neutrophils, and macrophages was increased in the blood of hypertensive patients compared with normotensive controls. In the current issue of the journal, Wang et al.13 extend the role of the CXCL1–CXCR2 axis to the development of cardiac hypertrophy and remodelling in hypertension using the same experimental design as in their previous study described above,12 with additional experiments and a higher dose of angiotensin II. In the present study, Cxcl1 was the most highly expressed chemokine in the heart of mice after 1 day of angiotensin II infusion compared with 11 other chemokines. Cxcr2 expression and infiltration of CXCR2-expressing monocytes, macrophages, and neutrophils were increased in the heart after angiotensin II infusion. Treatment with CXCL1 neutralizing antibodies, or the selective CXCR2 antagonist SB265610, or Cxcr2 knockout, reduced angiotensin II-induced BP elevation and prevented development of cardiac concentric hypertrophy with increased systolic function (increased ejection fraction and fractional shortening), cardiac fibrosis, and inflammation. Cxcr2 knockout blunted angiotensin II-induced cardiac infiltration of macrophages and neutrophils, but not T cells, which differs from their previous study and could be in part due to the higher angiotensin II dose used, since T cells do not express CXCR2.7 Bone marrow transplantation studies demonstrated that CXCR2-expressing immune cells are required for angiotensin II-induced hypertension and cardiac hypertrophy. In vitro, Cxcr2 knockout blunted the action of CXCL1 to drive macrophage migration and angiotensin II-induced macrophage activation. Furthermore, angiotensin II-induced neonatal cardiomyocyte hypertrophy and fibroblast differentiation into myofibroblasts was blunted when co-cultured with Cxcr2 knockout but not wild-type macrophages. However, it remains unclear why Cxcr2 expression is required in macrophages for angiotensin II-induced activation, or to cause cardiomyocyte hypertrophy and fibroblast differentiation. Finally, CXCL1 and the number of monocytes expressing CXCR2 were increased in the blood of hypertensive patients with heart failure, who presented dilated hypertrophy with decreased ejection fraction, in contrast to the increased ejection fraction found in the angiotensin II-infused mice. In conclusion, the study by Wang et al. offers new vistas on the role of chemokines and monocytes in the pathophysiology of cardiac hypertrophy in hypertension (Take home figure). Interfering with the CXCL1–CXCR2 axis prevented development of hypertension, which could be a therapeutic approach for prevention of cardiac hypertrophy and heart failure. This is supported by the SPRINT trial that showed that lowering systolic BP to <120 mmHg in hypertensive patients, compared with to <140 mmHg, reduced the rate of development of left ventricular hypertrophy14 and heart failure.15 Increased BP could have triggered the increase in cardiac Cxcl1 expression, followed by immune cell infiltration and cardiac injury leading to cardiac hypertrophy. In support of this, 3-day pressure overload induced by an abdominal aortic stenosis causes increased cardiac Cxcl1 expression.16 It will be important to take these studies further to determine whether new biomarkers or therapeutic targets can emerge from this work that will benefit patients with hypertension and heart failure. Role of chemokines and monocytes in the pathophysiology of cardiac hypertrophy in hypertension. Monocytes activated by the CXCL1–CXCR2 axis exert effects resulting in elevation of blood pressure (BP), which results in left ventricular hypertrophy (LVH) and eventually leads to heart failure. Alternatively, there may be a direct impact of the CXCL1–CXCR2–monocyte axis on the myocardium. Interfering with the CXCL1–CXCR2 axis could abrogate development of hypertension and cardiac hypertrophy, and prevent heart failure. The authors’ work was supported by Canadian Institutes of Health Research (CIHR) grants 102606 and 123465, CIHR First Pilot Foundation Grant 143348, a Canada Research Chair (CRC) on Hypertension and Vascular Research by the CRC Government of Canada/CIHR Program, and by the Canada Fund for Innovation (all to E.L.S.). Conflict of interest: none declared.

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