Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro.

Abstract

Numerous immature thymocytes undergo apoptosis and are rapidly engulfed by phagocytic thymic macrophages. The macrophage surface receptors involved in apoptotic thymocyte recognition are unknown. We have examined the role of the class A macrophage scavenger receptor (SR-A) in the engulfmnent of apoptotic thymocytes. Uptake of steroid-treated apoptotic thymocytes by thymic and inflammatory-elicited SR-A positive macrophages is partially inhibited by an anti-SR-A mAb and more completely by a range of scavenger receptor ligands. Thymic macrophages from mice with targeted disruption of the SR-A gene show a 50% reduction in phagocytosis of apoptotic thymocytes in vitro. These data suggest that SR-A may play a role in the clearance of dying cells in the thymus.Apoptosis or programmed cell death is now recognized as the physiologic mechanism by which large numbers of unwanted cells are deleted from the body (1). However, examination of tissues with ongoing programmed cell death highlights the scant evidence of dying cells in situ, a paradox that is explained by the existence of mechanisms for the specific and rapid removal of apoptotic cells by phagocytes. One of the earliest markers of commitment to undergo programmed cell death is phagocytosis of the apoptotic cell. In contrast to our knowledge of the process of apoptosis itself, relatively little is known of the clearance process by which dying cells are removed from the body in a manner that has no apparent inflammatory consequence. Examination of apoptotic cells in situ has shown that they are taken up and degraded by phagocytes, in particular macrophages (M+) (2). This activity can be observed in MO-like cells from species such as Drosophila, suggesting this is an important and conserved process (3) The process is specific, in that only cells committed to die are phagocytosed, and rapid, so that uptake is completed before the integrity of the apoptotic cell membrane is lost. Two essential components are required for the successful ingestion of the apoptotic cells: (i) specific receptor(s) on the surface of the phagocyte to mediate rapid recognition and ingestion and (ii) the presence of appropriate ligands on apoptotic cells that permit their distinction from healthy neighbors. The consensus that can be drawn from the relatively small number of reported studies on apoptotic cell recognition is that just like the regulation of apoptosis itself, it is complex and that there is not a single receptor-ligand system that explains apoptotic cell removal by all phagocytes (4).The thymus is the organ where the repertoire of mature T cells is selected from a much larger number of immature thymocytes and extensive apoptotic cell death occurs in the immature thymocyte populations. Although numerous immature thymocytes undergo apoptosis (5-7), few dead cells are observed in situ due to rapid engulfment by phagocytic M4 in the thymic stroma (8-10). A recent study (11), using the sensitive terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) technique ...

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

“…This hypothesis is supported by studies in which silica-induced inflammation and subsequent apoptosis overwhelmed macrophage capacity to ingest apoptotic neutrophils, resulting in persistent pulmonary inflammation in rats (66). Although the contributions of CD204 to apoptotic clearance in vivo have been difficult to determine and results are contradictory (35,49,50), further studies are necessary to clarify the contribution of CD204 to recognition of apoptotic neutrophils in the lungs and the identity of the apoptotic ligand.…”

“…Other naturally occurring ligands include polynucleotides and polysaccharides, gram-positive and gram-negative bacteria, and apoptotic cells (16,53,67). The versatile biological functions of SR include the clearance of pathological substances, host defense, cell adhesion, activation of intracellular signaling events, and cytokine production (21,26,50,51,57,65), although it is not yet clear how SR coordinate these immune and homeostatic functions.…”

The Class A Macrophage Scavenger Receptor Attenuates CXC Chemokine Production and the Early Infiltration of Neutrophils in Sterile Peritonitis

“…The phenotype of SR-A Ϫ/Ϫ mice did not reflect altered properties of neutrophils or reduced phagocytic clearance by RPM because the chemotactic movement of granulocytes to rMIP-2 was not affected, their ability to undergo apoptosis was not altered, nor was there an increased frequency of apoptotic cells within the inflamed peritoneum (19). Therefore, the peritonitis phenotype solely reflects enhanced recruitment.…”

“…This is probably why endotoxin, which binds to SR-A and other receptors, did not recapitulate the effects of TG, although it may be that SR-A plays only a minor role in the response of RPM to LPS. SR-A is best recognized as an endocytic receptor, but is involved in the phagocytosis of at least three other particles, apoptotic thymocytes (19), S. aureus (20), and Neisseria meningitidis (25). Unfortunately, at present, very little is known of the specific intracellular signaling events that follow ligation of the receptor (10), particularly in the context of phagocytosis.…”

The Naïve B Cells are the Lymphocytes with the Highest Anionic Phospholipid Binding Ratios

“…Many investigations have been done to study the receptors binding PL; in macrophage various candidate proteins have been evoked in the binding of cells expressing PS, but the nature of the receptor(s) that mediate PS recognition remains unclear; scavenger receptors, a5ß3 integrin, CD36 and CD14 have been reported to bind PS [24][25][26][27]. Class B scavenger receptors type I (SR-BI) and CD36 bind PS liposomes but not PC and PE liposomes [28].…”