Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains?

doi:10.1016/j.yjmcc.2015.10.029

Journal of Molecular and Cellular Cardiology

Volume 89, Part B, December 2015, Pages 136-145

https://doi.org/10.1016/j.yjmcc.2015.10.029 Get rights and content

Highlights

•
Monocyte/macrophage subsets linked to phases of cardiac injury.
•
Complex roles of macrophages linked to tissue injury, repair, fibrosis, and myocyte hypertrophy.
•
Monocyte/macrophage subset-specific therapies likely essential for efficacy in heart failure treatment

Abstract

The important contribution of monocytes and macrophages to cardiovascular disease and heart failure pathophysiology has attracted significant attention in the past several years. Moreover, subsets of these cells have been shown to partake in the initiation and exacerbation of several cardiovascular pathologies including atherosclerosis, myocardial infarction, pressure overload, cardiac ischemia and fibrosis. This review focuses on the role of monocytes and macrophages along the continuum to heart failure and the contribution of different cell subsets in promoting or inhibiting cardiac injury or repair. It outlines a primary role for the monocyte/macrophage system as an important regulator of cardiac inflammation and extracellular matrix remodelling in early and late stage heart disease with particular focus on phenotypic plasticity and the inflammatory and fibrotic functions of these cells. It also summarizes evidence from pre-clinical and clinical studies evaluating monocyte type regulation and its functional significance for development of cardiovascular disease and heart failure. Finally, current and prospective therapeutic approaches based on monocyte and macrophage manipulation for the treatment of cardiovascular disease and heart failure are discussed. Based on these data, future work in this fertile research area may aid in identifying potential diagnostic biomarkers and novel therapies for chronic heart failure.

Section snippets

Cardiovascular disease and inflammation

Diseases of the cardiovascular system including ischaemic heart disease, cerebrovascular disease, hypertension, heart failure (HF) and rheumatic disease are the underlying cause for 29.2% (16.7 million) of total global deaths annually according to statistics of the World Health Organization. Approximately a quarter of all deaths occur as a result of chronic diseases including HF, with equal contribution of HF with Preserved and Reduced Ejection Fraction (HFPEF and HFREF). Insufficient knowledge

Monocytes and macrophages — the effector cells of inflammation and coordinators of wound healing in cardiovascular disease and heart failure

Monocytes are components of the innate and adaptive immune systems with primary functions in immune defence, inflammation and tissue remodelling. As regulators of immune responses, monocytes protect the host against foreign pathogens in a non-antigen-specific manner either by direct pathogen elimination (depending on specific interactions between pattern recognition receptors including toll-like receptors (TLR), the lipopolysaccharide co-receptor CD14, and scavenger receptors) or by production

Monocyte and macrophage subsets

At least three subsets of monocytes with distinct phenotypic and functional characteristics exist in human peripheral blood (Fig. 1).

Monocyte subsets are best differentiated on the basis of surface expression of the lipopolysaccharide co-receptor CD14 and the Fcγ receptor III CD16 and are classified as classical, CD14 ++CD16 −, intermediate CD14 ++CD16 +, or alternative, CD14 + CD16 ++ monocytes [38], [39]. Classical monocytes make up for approximately 85–90% of all blood monocytes whilst

Monocyte and macrophage subsets in animal models and patients with CVD and heart failure

A limited number of pre-clinical and clinical studies have been performed to characterize monocyte subsets in the blood of patients with cardiovascular disease and HF and study the contribution of these to the pathophysiology of HF (Table 1).

Most pre-clinical studies examining monocyte subtype and function pertain to animal models of atherosclerosis and myocardial infarction. Nahrendorf et al. described that the healing process in the mouse heart following myocardial infarction requires

Monocyte and macrophage-based therapeutic approaches in heart disease and failure

Given the importance of monocyte/macrophage heterogeneity and multi-functionality, the concepts of monocyte/macrophage plasticity and manipulation for therapeutic application in the fields of chronic inflammatory diseases and cancer are gaining considerable scientific and clinical interest. Unfortunately, due to the complexity and subtlety of the field, the literature is rather limited [46], [67].

Ample evidence has shown beneficial effects of blocking monocyte/macrophage infiltration and

Summary

When considering the role of monocytes and macrophages in the progression to heart failure (Fig. 2) it is clear that any therapeutic intervention has to be targeted specifically to the stage and type of disease.

From a simplistic model point of view it would be apparent that attenuating M1 macrophage activity immediately following myocardial infarction has the potential to minimize tissue injury and cell damage that may be caused by an uncontrolled M1-driven response. However, given the

Conclusion

The monocyte/macrophage system is an important innate immune mechanism to battle infection and malignancy. A perhaps equally important function is its regulation and tuning of inflammatory, wound repair and fibrotic processes and therefore tissue remodelling and repair in systemic diseases including cardiovascular disease. Here we summarize the most recent knowledge on monocytes and macrophages in the field of cardiac inflammation, cardiac fibrosis and heart failure including novel findings on

Disclosures

None.

Acknowledgements

None.

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¹: Present address for Stephen Horgan is Brigham and Women's Hospital, Boston, Massachusetts, USA.

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Review articleMonocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains?

Highlights

Abstract

Section snippets

Cardiovascular disease and inflammation

Monocytes and macrophages — the effector cells of inflammation and coordinators of wound healing in cardiovascular disease and heart failure

Monocyte and macrophage subsets

Monocyte and macrophage subsets in animal models and patients with CVD and heart failure

Monocyte and macrophage-based therapeutic approaches in heart disease and failure

Summary

Conclusion

Disclosures

Acknowledgements

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Mol. Cell. Cardiol.

Int. J. Cardiol.

Blood

J. Thromb. Haemost.

J. Am. Coll. Cardiol.

Immunity

Trends Immunol.

Trends Immunol.

Immunity

Clin. Immunol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Thromb. Haemost.

J. Card. Fail.

Kidney Int.

J. Mol. Cell. Cardiol.

Int. J. Biochem. Cell Biol.

J. Am. Coll. Cardiol.

Targeted anticytokine therapy and the failing heart

Am. J. Cardiol.

Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches

Am. J. Cardiol.

Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology

Eur. J. Heart Fail.

Immune activation in chronic heart failure

Am. J. Cardiol.

Inflammatory mediators and the failing heart: past, present, and the foreseeable future

Circ. Res.

A glossary of circulating cytokines in chronic heart failure

Eur. J. Heart Fail.

Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction

Eur. J. Heart Fail.

The origin and kinetics of mononuclear phagocytes

J. Exp. Med.

Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions

Circulation

Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis

J. Exp. Med.

Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation?

Hypertension

Inflammatory cells and myocardial fibrosis: spatial and temporal distribution in renovascular hypertensive rats

Cardiovasc. Res.

Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis

Hypertens. Res.

Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload

Histochem. Cell Biol.

Monocytes in heart failure: relationship to a deteriorating immune overreaction or a desperate attempt for tissue repair?

Cardiovasc. Res.

The role of monocytes and inflammation in the pathophysiology of heart failure

Eur. J. Heart Fail.

Macrophages: master regulators of inflammation and fibrosis

Semin. Liver Dis.

Transcriptional regulation of macrophage polarization: enabling diversity with identity

Nat. Rev. Immunol.

Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?

Eur. J. Heart Fail.

Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes

PLoS ONE

Macrophage plasticity and polarization: in vivo veritas

J. Clin. Invest.

Review article
Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains?