Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences

Apoptosis, a genetically programmed cell death conserved throughout phylogeny, provides a counterbalance to mitosis in the regulation of tissue growth and homeostasis (1, 2). Interest in and knowledge of the mechanisms mediating the induction and execution of the death program have blossomed in the last decade and a half. Engulfment of apoptotic bodies and debris represents the denouement of the death program for most cells in multicellular organisms. Macrophages and other cells manifesting their primitive phagocytic potential clear apoptotic bodies from tissues, preventing their lysis and the consequent release of toxic or immunogenic intracellular components. By inducing the release of mediators such as TGF-β, IL-10, prostaglandin E2 (PGE2), and others, clearance of apoptotic cells also sets up an anti-inflammatory milieu within the tissue (reviewed in refs. 3, 4). However, phagocytic clearance is not merely a silent process with respect to inflammation and immunity but is also actively anti-inflammatory. In spite of its critical importance to tissue and host homeostasis, clearance of apoptotic cells is poorly understood, and studies devoted to elucidating the mechanisms mediating recognition and engulfment have lagged behind those probing the induction and execution of the death process itself. This situation is finally changing as we begin to unravel the mechanisms mediating clearance of apoptotic cells. Many of the macrophage receptors that contribute to apoptotic cell recognition are critical players in innate immunity. These include certain lectins and integrins, the class A and class B scavenger receptors (see Platt and Gordon, this Perspective series, ref. 5; and Krieger, this series, ref. 6), receptors for oxidized LDL, including CD68 and lectin-like oxidized LDL receptor-1 (LOX-1), some of the receptors for complement-derived proteins, and the endotoxin receptor CD14 (reviewed in ref. 7). Paradoxically, however, when microbial organisms or their products are engulfed via these receptors, inflammation results, and in many cases, acquired immunity is stimulated. In contrast, uptake of apoptotic cells is generally noninflammatory and thereby avoids activation of an acquired immune response. Our task is to understand and explain these diametrically opposed reactions to stimulation of the same receptors.