Shedding light on impaired efferocytosis and nonresolving inflammation

Abstract

Nonresolving inflammation contributes to tissue damage and organ dysfunction in a wide array of pathologies, including cardiovascular disease. At the interface between inflammation and inflammation-resolution is the macrophage. Macrophage engulfment of apoptotic cells (efferocytosis) during immune cell turnover triggers activation of intra- and inter-cellular immunosuppressive signaling networks. In diseases of aging and obesity, accumulating evidence indicates that efferocytosis is impaired; the underlying mechanisms of which are unclear. In the current issue of Circulation Research, Driscoll et al., reveal that deficiency of the metalloproteinase ADAM17 prevents shedding of the apoptotic cell receptor CD36 from macrophages to enhance efferocytosis and inflammation resolution during peritonitis. These findings implicate proteolysis of apoptotic cell receptors as one explanation for defective efferocytosis-directed inflammation resolution during disease. Future studies are warranted to test the significance of these findings during cardiovascular syndromes and in other cases of nonresolving inflammation.

Keywords: ADAM17; CD36; efferocytosis.

Figure 1. Proteolysis of CD36 by ADAM17 delays inflammation resolution by inhibiting efferocytosis

ADAM17 (green) cleaves membrane bound CD36 on macrophages (MΦs), leading to shedding of soluble CD36 (sCD36) into the extracellular milieu. Loss of CD36 reduces efferocytosis, i.e., macrophage engulfment of apoptotic cells (ACs), and in turn delays inflammation resolution. Absence of ADAM17 (ADAM17-/-) in contrast promotes efferocytosis and an anti-inflammatory response in MΦs, thereby enhancing inflammation resolution.