Abstract
The rapid and efficient clearance of apoptotic cells results in the elimination of auto-antigens and provides a strong anti-inflammatory and immunosuppressive signal to prevent autoimmunity. While professional and non-professional phagocytes utilize a wide array of surface receptors to recognize apoptotic cells, the recognition of phosphatidylserine (PS) on apoptotic cells by PS receptors on phagocytes is the emblematic signal for efferocytosis in metazoans. PS-dependent efferocytosis is associated with the production of anti-inflammatory factors such as IL-10 and TGF-β that function, in part, to maintain tolerance to auto-antigens. In contrast, when apoptotic cells fail to be recognized and processed for degradation, auto-antigens persist, such as self-nucleic acids, which can trigger immune activation leading to autoantibody production and autoimmunity. Despite the fact that genetic mouse models clearly demonstrate that loss of PS receptors can lead to age-dependent auto-immune diseases reminiscent of systemic lupus erythematosus (SLE), the link between PS and defective clearance in chronic inflammation and human autoimmunity is not well delineated. In this perspective, we review emerging questions developing in the field that may be of relevance to SLE and human autoimmunity.
Highlights
The clearance of apoptotic cells by phagocytic cells is critically important to maintain homeostasis in multicellular organisms
We review emerging questions developing in the field that may be of relevance to systemic lupus erythematosus (SLE) and human autoimmunity
CONCLUDING REMARKS While the link between defective efferocytosis and auto-immune disease and advanced atherosclerosis has been made, and validated in experimental animal models, where and when this circuitry fails in human disease has not been firmly established by genetic causation studies
Summary
The clearance of apoptotic cells by phagocytic cells (a process called efferocytosis to distinguish the processing of apoptotic cells from other phagocytic processes) is critically important to maintain homeostasis in multicellular organisms. The fact that blockage of PS on the apoptotic cell prevents many of the anti-inflammatory consequences of efferocytosis, combined with observations that knockout of several PS receptors and PS opsonins (soluble factors that link PS on apoptotic cells to receptors) lead to failed efferocytosis, chronic inflammation, and age-dependent autoimmunity [4] has led many investigators to a conceptual framework that externalized PS functions as a dampening platform for negative immune regulation In this capacity, externalized PS functions both as an “eat-me” signal for efferocytosis, and as an “inflammo-suppression” signal that promotes tolerance for both immune cells and non-immune bystander cells that come in direct contact with PS externalized membranes [2, 19, 20]. Despite convincing evidence as gleaned from knockout studies in mouse, identifying links between defective PS recognition and/or signaling and human autoimmunity has been surprisingly enigmatic (Table 1)
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