Contribution of Defective PS Recognition and Efferocytosis to Chronic Inflammation and Autoimmunity

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.

Cell death, clearance and immunity in the skeletal muscle

“…[85][86][87][88] Relatively little is known on the role of phagocytic tags in the skeletal muscle. Exposure of anionic phospholipids, such as phosphatidylserine (PS), is among the best-characterized events involving in apoptotic cell recognition.…”

Rab17 mediates differential antigen sorting following efferocytosis and phagocytosis

“…7, 8 Apoptotic cells that are not cleared undergo secondary necrosis, driving inflammation and autoimmunity through the release of self-antigens and proinflammatory intracellular contents into the extracellular milieu. 9 Efferocytosis is a particularly important physiological function of macrophages, with defective macrophage efferocytosis implicated in the development of a number autoimmune and inflammatory disorders including systemic lupus erythematosus 10, 11, 12 and atherosclerosis. 6, 13, 14, 15, 16 Despite recognition of the importance of efferocytosis in the maintenance of homeostasis, the mechanisms regulating efferocytosis remain poorly elucidated.…”

“…It is thought that the molecular mechanisms of efferocytosis resembles those of phagocytosis, with the important distinction that the ultimate outcome of phagocytosis is the induction of inflammation and antigen presentation, whereas efferocytosis is immunologically silent. 2, 10, 17 While a number of ligands, mediators and receptors that regulate efferocytosis have been identified and characterized, 10 little is known of the maturation process that degrades efferocytosed cells, or the processes that determine the ultimate fate of degraded apoptotic cells.…”

Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response

“…Although an exact biophysical or structural basis for why non-γ-carboxylated Gas6 binds but does not activate TAMs is not yet available, one possibility is that N-terminal γ-carboxylation allows for ligand-induced conformational changes and/or dimerization as a pre-requisite for receptor activation. Furthermore, it is well known that γ-carboxylation facilitates Gla domain binding to calcium that in turn allows its interaction with the anionic phospholipids, such as PS; which is known to be externalized on apoptotic cells, apoptotic blebs, exosomes, stressed tumor cells and vasculature, and on enveloped virus [56,57,58,59]. However, as noted above, the exact mechanisms by which PS/Gla interactions at the N-termini are communicated to the LG domain for ligand binding and conformational-induced receptor dimerization awaits further experimentation.…”