During inflammation and infection, we are simultaneously confronted with both self and non-self in form of dying cells and microbes, respectively. Mechanisms that facilitate the non-immunogenic clearance of self-antigens derived from apoptotic and necrotic cells and that, in parallel, allow the initiation of an immune response against invading pathogens are incompletely understood. Recent data from our laboratory show that the immune system actively sorts apoptotic cells (ACs) and bacteria into distinct subspecies of phagocytes thereby enabling a segregated processing of self and non-self as well as a differential immune response against these two entities. During inflammation, ACs were cleared by tissue resident macrophages (resMφ) that performed a non-immunogenic disposal of self antigens, whereas bacteria were preferentially ingested by monocyte-derived inflammatory macrophages. We identified the enzyme 12/15-lipoxygenase and the nuclear receptor Nr4a1, both specifically expressed by resMφ, as key factors that control the coordinated and non-immunogenic phagocytosis of ACs by these specialized macrophage subset. Incorrect sorting and aberrant uptake of AC-derived self-antigens by pro-inflammatory and immunocompetent phagocytes, however, resulted in the break of self-tolerance and autoimmunity. Our data thus demonstrate the importance of a sorted clearance of ACs for the maintenance of immunologic self-tolerance.
Disclosure of Interest None declared