Dancing with the Scars: Choreography of the Macrophage Two Step After Myocardial Infarction

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Science Translational Medicine  02 Apr 2014:
Vol. 6, Issue 230, pp. 230ec59
DOI: 10.1126/scitranslmed.3009041

Ischemic vascular disease is the leading cause of disability in both industrialized and developing countries. Ischemic injury in the heart can lead to a myocardial infarction (MI) followed by an immune response in which macrophages are key players. The two main types of macrophages—proinflammatory (M1) or reparative (M2)—must “dance” in a balanced way to properly heal an area of tissue affected by the infarction. If the macrophages are out of step, pathological cardiac remodeling can ensue, leading to heart failure. A step toward understanding the choreography of the M1 and M2 responses to infarction has now been reported by Hilgendorf et al. These authors identify the nuclear receptor NR4A1/Nur77 as a molecular switch that composes the M1 and M2 response to myocardial infarction.

Hilgendorf et al. cleverly used Nr4a1–/– mice to examine the origins and roles of M1 and M2 subsets in response to experimentally induced MI; these mice are missing the mouse equivalent of M2 macrophages (Ly-6Clow). They noted that after an infarction, Nr4a1–/– mice produced a more robust early M1 response (Ly-6Chigh) than that of wild-type mice. After this acute response, the M1 monocytes differentiated into M2-type macrophages that, surprisingly, retained a proinflammatory phenotype. Moreover, as shown with echocardiography, Nr4a1–/– mice exhibited worse cardiac structure and function at long time periods after MI than did wild-type mice. The investigators concluded that M1 monocytes can differentiate into M2 macrophages, and NR4A1 choreographs the early inflammatory (M1 dominated) and later reparative responses (M2 mediated) in the infarcted myocardium.

In the future, translational researchers can examine the effect of NR4A1 regulation and—perhaps more important—genetic variation on macrophage subset participation in the response to MI. Moreover, NR4A1 is a potentially druggable target in the battle against unfavorable post-MI cardiac remodeling. This work has identified an intriguing choreographer with the skill to balance the monocyte-macrophage “two-step.”

I. Hilgendorf et al., Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ. Res. 10.1161/circresaha.114.303204 (2014). [Abstract]

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