Physiological Roles and Regulation of NCOA4 in Macrophages

Abstract

Phagocytosing macrophages are critical to systemic iron homeostasis owing to their capability to recycle iron from senescent RBCs and store iron under systemic distress. NCOA4 has recently been identified as a key regulator of ferritin, mediating its degradation via ferritinophagy. Yet, its function in macrophages remains unclear. The present studies employed a cell culture model of J774 macrophages, to examine the role and regulation of macrophage NCOA4 by iron status, red cell iron recycling, and inflammation. Macrophage NCOA4 is responsive to iron status and inversely related to ferritin abundance. By erythrophagocytosis, ferritin peaks at 12 hours with subsequent decrease at 24 hours which is NCOA4-dependent. Hepcidin activity repressed NCOA4 preventing the turnover of ferritin between 12 and 24 hours in erythrocyte laden macrophages. Macrophages were treated with LPS, which decreased both NCOA4 transcript and protein abundance. Altogether our studies demonstrate an active role of NCOA4-mediated ferritinophagy in macrophage iron homeostasis.