CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload

Patel, Bindiya; Bansal, Shyam S.; Ismahil, Mohamed Ameen; Hamid, Tariq; Rokosh, Gregg; Mack, Matthias; Prabhu, Sumanth D.

doi:10.1016/j.jacbts.2017.12.006

Cited by 224 publications

(216 citation statements)

References 39 publications

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“…Myeloid cells that include monocytes and monocyte-derived DCs have indeed been reported to be major producers of CXCL9 and CXCL10 in the inflamed brain (27). Recent studies indicate that CCR2 + myeloid cells precede CD4 + T cell infiltration in the heart in response to TAC, and their depletion results in impaired CD4 + T cell expansion in the mLNs and subsequent recruitment to the heart (40,41). Our data, in line with these studies, demonstrate that a high percentage of CCR2 + -recruited monocytes and macrophages are indeed a source of CXCL10 and that CCR2 + macrophages also produce CXCL9.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

Ngwenyama¹,

Salvador²,

Velázquez³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

Ngwenyama¹,

Salvador²,

Velázquez³

et al. 2019

JCI Insight

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“…In the premalignant syndrome of clonal hematopoiesis of indeterminate potential (CHIP), inactivating mutations in genes controlling hematopoietic stem cell turnover and differentiation leads to enhanced proliferation of myeloid cells with pro-inflammatory properties, and to an increased T helper 17 (Th17) / regulatory T cell (Treg) ratio [15] (first hit). Furthermore, pro-inflammatory circulating immune cells are recruited into the heart by danger signals produced in the myocardium in response to traditional risk factors such as elevated BP, aortic valve stenosis, smoking and/or aging (second hit), with endothelial activation facilitating the immune cell influx [9,[16][17][18][19][20]. Once infiltrated into the myocardial interstitium, monocytes become activated and aid in the recruitment and activation of Th1 and Th17 cells, via chemotactic molecules and antigen presentation [16,18,21], respectively.…”

Section: Introductionmentioning

confidence: 99%

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Sava

Pepine

March

2020

JCM

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Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo, thus they may efficiently target immune dysregulation in HFpEF and stop disease progression.

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“…A persistent inflammatory response to injury (ischaemic, infectious, pressure, or volume overload), or a failure to resolve inflammation following acute injury, can lead to chronic expression of pro‐inflammatory cytokines that have been suggested to contribute to HF progression . Moreover, the failing heart exhibits expanded populations and activation of both innate and adaptive immune cells that are essential contributors to progressive LV remodelling . Pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 are associated with increasing severity of HF and contribute to progressive LV remodelling and systolic dysfunction …”

Section: Discussionmentioning

confidence: 99%

“…Heart failure (HF) is a pro‐inflammatory state . Several pathways including pro‐inflammatory cytokines and innate and adaptive immune cellular responses have been implicated in HF . It is also evident that dysregulated inflammation and immune activation contribute importantly to progressive left ventricular (LV) remodelling and dysfunction .…”

Section: Introductionmentioning

confidence: 99%

Effect of immunomodulation on cardiac remodelling and outcomes in heart failure: a quantitative synthesis of the literature

et al. 2020

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Aims Immunomodulation in heart failure (HF) has been studied in several randomized controlled trials (RCTs) with variable effects on cardiac structure, function, and outcomes. We sought to determine the effect of immunomodulation on left ventricular ejection fraction (LVEF), LV end-diastolic dimension (LVEDD), and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF) through meta-analyses and trial sequential analyses (TSAs) of RCTs. Methods and results PubMed, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov were systematically reviewed to identify RCTs that studied the effects of immunomodulation in patients with HFrEF. The primary endpoint in this analysis was change in LVEF. Secondary outcomes were changes in LVEDD and all-cause mortality. TSA was used to quantify the statistical reliability of data in the cumulative meta-analyses. Nineteen RCTs with 1341 HFrEF subjects were eligible for analyses. The aetiology of HF, specific immunomodulation strategy, and treatment duration were variable across trials. Immunomodulation led to a greater improvement in LVEF [mean difference: +5.7% 95% confidence interval (CI): 3.0-8.5%, P < 0.001] and reduction in LVEDD (mean difference: À3.7 mm, 95% CI: À7.0 to À0.4 mm, P = 0.028) than no immunomodulation in meta-analyses and TSAs. We observed a non-significant decrease in all-cause mortality among those on immumomodulation (risk ratio: 0.7, 95% CI: 0.4-1.3, P = 0.234), but the Z-curve for cumulative treatment effect of immunomodulation in the TSA did not cross the boundary of futility. Conclusions Immunomodulation led to improved cardiac structure and function in patients with HFrEF. While these benefits did not translate into a significant improvement in mortality, our analysis suggests that larger studies of targeted immunomodulation are needed to understand the true benefits.

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CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload

Abstract: Visual Abstract

Cited by 224 publications

References 39 publications

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Effect of immunomodulation on cardiac remodelling and outcomes in heart failure: a quantitative synthesis of the literature

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