Efferocytosis by Paneth cells within the intestine

Summary. Apoptotic cells are quickly and efficiently engulfed and removed via the process of efferocytosis by either professional phagocytes, such as macrophages, or non-professional phagocytes, including epithelial cells.^1,2 In addition to debris removal, a key benefit of efferocytosis is that phagocytes engulfing apoptotic cells release anti-inflammatory mediators^3,4 that help reduce local tissue inflammation;⁵ conversely, accumulation of uncleared apoptotic cells predisposes to a pro-inflammatory tissue milieu.^6-8 Due to their high proliferative capacity, intestinal epithelial cells (iECs) are sensitive to inflammation, irradiation, and chemotherapy-induced DNA damage, leading to apoptosis. Mechanisms of iEC death in the context of irradiation has been studied,^9,10 but phagocytosis of dying iECs is poorly understood. Here, we identify an unexpected efferocytic role for Paneth cells, which reside in intestinal crypts and are linked to innate immunity and maintenance of the stem cell niche in the crypt.^11,12 Through a series of studies spanning in vitro efferocytosis, ex vivo intestinal organoids ("enteroids"), and in vivo Cre-mediated deletion of Paneth cells, we show that Paneth cells mediate apoptotic cell uptake of dying neighbors. The relevance of Paneth-cell-mediated efferocytosis was revealed ex vivo and in mice after low-dose cesium-137 (¹³⁷Cs) irradiation, mimicking radiation therapies given to cancer patients often causing significant apoptosis of iECs. These data advance a new concept that Paneth cells can act as phagocytes and identify another way in which Paneth cells contribute to the overall health of the intestine. These observations also have implications for individuals undergoing chemotherapy or chronic inflammatory bowel disease.