Resident Cardiac Macrophages Mediate Adaptive Myocardial Remodeling
Posted on: 30 April 2021 , updated on: 28 December 2021
Preprint posted on 30 January 2021
Article now published in Immunity at http://dx.doi.org/10.1016/j.immuni.2021.07.003
CCR2- macrophages to mend a broken heart: How to sense mechanical strain and translate into adaptive cardiac remodeling and angiogenesis.
Selected by Laura Alonso-Herranz
Categories: cell biology, immunology, pathology
Background
Studies dating back to 1980 anticipated that the adult mammalian heart contains several cell populations other than cardiomyocytes, including macrophages [1]. However, thanks to the development of state-of-the-art tools (e.g. genetic fate mapping, advanced flow cytometry, single-cell RNA-sequencing), we are now becoming conscious of the abundance, functional heterogeneity, and diverse ontogeny of cardiac macrophages.
During embryonic development, yolk sac and fetal liver precursors seed the myocardium and give rise to macrophages that are maintained through local proliferation in homeostatic conditions. These macrophages persist into adulthood, although they show declining self-renewal with age and are progressively replaced by definitive hematopoietic progenitor-derived macrophages [2]. Murine cardiac macrophages differ in the expression of the surface markers CC-chemokine receptor 2 (CCR2) and major histocompatibility complex II (MHC-II). Previous work by this group has shown that the human myocardium also contains separate subsets of CCR2- and CCR2+ macrophages, which are functionally analogous to the healing CCR2- macrophages and the inflammatory CCR2+ macrophages, respectively, in the murine heart [3].
Recent evidence supports that cardiac resident macrophages (CRMs) make a seminal contribution to cardiac development, composition, and function. They participate in essential homeostatic functions, including immune surveillance, facilitation of electrical conductivity, and preservation of cardiac metabolism stability [4, 5]. Furthermore, CCR2- macrophages, but not CCR2+ macrophages, contribute to coronary development and neonatal heart regeneration [6, 7]. However, little is known about the contribution of these CCR2- macrophages to pathological contexts. In this preprint, Wong et al. aim to describe novel roles of CCR2- macrophages using a mouse model of human dilated cardiomyopathy (Tnnt2ΔK210/ ΔK210 mouse).
Key findings
The main findings of the current study can be summarized as follows:
- First, the authors describe macrophage heterogeneity in chronic heart failure and, by means of genetic lineage tracing, demonstrate that CCR2- macrophages are a mixed population of embryonic- and definitive hematopoiesis-derived macrophages, which are maintained by local proliferation independently of blood monocytes. Interestingly, the disparate origin of CCR2- macrophages (definitive or extra-embryonic hematopoiesis) does not seem to endow them with distinct functions. In contrast, transcriptomic analysis shows different functions for CCR2- and CCR2+ macrophages, with CCR2- macrophages involved in cell migration and cell adhesion.
- Selective CCR2- macrophage deletion with the CD169-DTR mouse model (a transgenic line in which the receptor for diphtheria toxin is expressed in cardiac macrophages and thus specific cell depletion can be achieved upon diphtheria toxin injection) dramatically accelerates mortality in mice with chronic heart failure, indicating a beneficial role of CCR2- macrophages in this context. Despite no alteration in cardiac contractility, CCR2- macrophage depletion attenuates cardiac remodeling and blunts the expansion of the coronary vasculature in chronically failing hearts.
- Cardiac tissue immunostaining, electron microscopy, ex vivo two-photon microscopy, and in vitro experiments revealed that, while CCR2- macrophages establish physical contact with adjacent cardiomyocytes through focal adhesion complexes, CCR2- macrophages do not directly contact cardiomyocytes.
- In vitro mechanical stretching experiments showed that macrophages are involved in the detection of mechanical strain via the Transient Receptor Potential Cation Channel TRPV4, which translates into an enhanced expression of pro-angiogenic and remodeling factors.
- Finally, the authors performed pharmaceutical intervention studies to assess the functional relevance of TRPV4 in vivo. These experiments demonstrate that TRPV4 regulates the expression of the pro-angiogenic factor IGF1 in cardiac macrophages. In addition, inhibition of TRPV4 in chronically failing hearts mimics the phenotype described for mice with CCR2- macrophage depletion (reduced LV dilation and impaired vascular network expansion), suggesting that TRPV4 action constrains to this subset of macrophages.
In conclusion, Wong et al. propose that, in the failing heart, CCR2- macrophages sense mechanical stretch thanks to their interactions with neighboring cardiomyocytes, get activated via TRPV4, and secrete growth factors that promote adaptive left ventricular remodeling and coronary angiogenesis. Thus, they ultimately contribute to the survival of the chronically failing heart.
Why I chose this preprint
When I saw that this preprint was coming from the Lavine lab I was thrilled to read it. A line of research of the lab is devoted to describing the diversity, ontogeny, and function of cardiac resident macrophages (CRMs). This lab has contributed with seminal papers to uncover the functions of CRMs, such as facilitation of electrical conduction, coronary development and maturation, and cell junction formation.
On this occasion, Wong et al. shed light on the pathophysiological role of CRMs in a mouse model of human chronic heart disease and delineated the molecular mechanism by which macrophages detect mechanical strain and promote beneficial cardiac remodeling and angiogenesis.
Questions I would ask the authors
- In the introduction, the authors compared physiological versus maladaptive cardiac remodeling, highlighting that transcriptional activation patterns differ from one to another. Do they hypothesize that TRPV4 activation in CRMs is exclusive for chronic heart failure and would not be seen, for example, in exercise-conditioned cardiac hypertrophy?
- Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction [8, 9]. How inconvenient could be the lack of interstitial fibrosis in Tnnt2ΔK210/ΔK210 mice for the current study when compared to other chronic heart failure models that induce myocardial fibrosis (e.g. transverse aortic constriction (TAC) or isoproterenol infusion)?
- Tnnt2ΔK210/ΔK210 KO mice are already born with impaired myocardial contractility and heart function. Have the authors considered the additional use of an inducible model of cardiomyopathy to corroborate the findings?
- Why have the authors chosen to perform a microarray instead of RNA-seq, which will be more informative? Transcriptional analysis reveals alternative functions for CCR2- and CCR2+ macrophage populations. Have the authors thought about specific functional in vitro experiments to further support this finding?
References
- Nag, A.C., Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios, 1980. 28(109): p. 41-61.
- Molawi, K., et al., Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med, 2014. 211(11): p. 2151-8.
- Bajpai, G., et al., The human heart contains distinct macrophage subsets with divergent origins and functions. Nat Med, 2018. 24(8): p. 1234-1245.
- Nicolás-Ávila, J.A., et al., A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart. Cell, 2020. 183(1): p. 94-109.e23.
- Hulsmans, M., et al., Macrophages Facilitate Electrical Conduction in the Heart. Cell, 2017. 169(3): p. 510-522.e20.
- Leid, J., et al., Primitive Embryonic Macrophages are Required for Coronary Development and Maturation. Circ Res, 2016. 118(10): p. 1498-511.
doi: https://doi.org/10.1242/prelights.28768
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