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Macrophages that fix or break the heart

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Science Immunology  06 Jul 2018:
Vol. 3, Issue 25, eaau2828
DOI: 10.1126/sciimmunol.aau2828

Abstract

Human myocardium contains different types of macrophages with heterogenous functions and origins.

Although recent mouse studies have established that most tissues, including heart, contain functionally heterogenous subsets of resident macrophages, knowledge about human tissue macrophage heterogeneity has been limited. Bajpai and colleagues analyzed macrophages in human myocardium obtained from patients with dilated and ischemic cardiomyopathies, including left ventricular cores removed at the time of assist device placement [left-ventricular assist device (LVAD) cores], and from hearts explanted at time of transplantation. Flow cytometry and immunohistochemistry revealed the presence of C-C chemokine receptor type 2 (CCR2)– macrophages and CCR2+ monocytes and macrophages. Sorted CCR2+ cardiac macrophages produced more interleukin-1 (IL-1) and C-C motif chemokine ligand 7 (CCL7) thanCCR2- macrophages. Cultured slices of human heart increased expression of IL-1β, CCL7, and tumor necrosis factor messenger RNA over 24 hours, likely in response to myocyte death, and IL-1 colocalized with CCR2+ CD68+ cells. Analysis of endomyocardial biopsies of male patients about eight years after receiving female donor heart transplants showed that about 99% of the CCR2– macrophages did not have Y chromosomes—that is, they were not derived from the recipients’ circulating monocytes—whereas about 30% CCR2+ macrophages were Y chromosome positive. Both the CCR2+ and CCR2– populations contained significant numbers of proliferating cells, but there were more in the CCR2+ population. Gene expression array analyses of the macrophages from failing hearts supported the hypothesis that CCR2+ monocytes, CCR2+ macrophages, and CCR2− macrophages are distinct populations; that CCR2+ monocytes and CCR2+ macrophages are closely related, both with inflammatory functions; and that CCR2− macrophages express genes known to mediate tissue repair. The authors also determined that CCR2+ macrophage abundance inversely correlated with improvement of LV function while patients were on assist devices, thereby establishing a relationship of cardiac macrophage phenotype and myocardial repair. This paper is important, because it confirms that the basic cardiac macrophage subset biology described in mouse studies is conserved in humans, shows different functions and origin of human heart macrophages, and establishes the need for further studies of macrophage phenotypes to better understand heart failure. One limitation of the findings is the lack of data on macrophages in nonfailing, non-transplanted human heart tissue, which obviously is difficult to obtain.

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