apoptosis or programmed cell death occurs during embryogenesis , normal cell turnover , and as a consequence of immune mediated , infectious , or inflammatory effects . clearance of intact apoptotic cells ( acs ) * by phagocytes protects surrounding tissues from intracellular factors and reduces the likelihood of tissue damage caused by inappropriate autoimmune responses . acs exhibit numerous changes including the surface exposure of phosphatidylserine ( ps ) and alteration of membrane carbohydrates . multiple ligands and receptors have been implicated in the recognition and uptake of acs ( fig . 1 ) , but attempts to assign function to discrete receptors has proven difficult . in this issue , hoffmann et al . ( 2001 ) assess the relative role of various receptors through ac surrogates that ligate individual receptors . these surrogates consist of biotinylated human erythrocytes coated with avidin ( eba ) , which are bound to a biotinylated protein ligand or antireceptor antibody , creating ebab - x . binding to and internalization of ebab - x by macrophages and other cells is evaluated in the absence of serum ( to prevent interference of serum proteins ) and is distinguishable by microscopy . these receptors interact with their ligands on the ac either directly or via bridging proteins . the dominance , cooperation , and redundancy amongst these receptors are discussed in the text . mbl , spa , bc , and c1q are defense collagens , which bridge ac to phagocytes via calretculin and cd91 . la and tsp are putative bridging molecules for the v3 and v5 integrins , respectively . specific gene 6 , appears to bridge ps with receptor tyrosine kinases such as mer . surprisingly , individual or multiple engagement of the ac receptors cd36 , the v3 and v5 integrins , cd14 , and cd68 caused tethering of erythrocytes but little internalization . in contrast , engagement of the ps receptor ( psr ) alone through ps - coated erythrocytes induced neither tethering nor uptake . however , ligation of both psr and other receptors ( including receptors not normally involved in phagocytosis ) converted the adhesion mediated by the latter to ingestion . direct ligation of psr produced tgf , supporting earlier data that psr modulation is critical for inducing immunosuppressive cytokines . signal , which stimulates the internalization of acs , including bystander cells , that are  tethered  through other recognition receptors . the observation that acs which do not express ps are poorly phagocytosed ( fadok et al . , 2001 ) suggests that ps  psr interactions play a crucial regulatory role in dead cell clearance . psr engagement tickles the phagocyte to take up tethered apoptotic cells , including bystander cells , by macropinocytosis . internalization requires reorganization of the actin cytoskeleton through activation of the rho gtpases rac1 , and cdc42 , and the wasp . in this scenario , psr also has an immunoregulatory role . signaling through this receptor leads to secretion of immunosuppressive cytokines such as tgf- and possibly pge2 , il-10 , and platelet - activating factor ( paf ) . the  tether and tickle the tethering step makes it feasible for signaling to proceed through low avidity ps  psr interactions . specificity and regulation is provided to the multiple recognition mechanisms for ac uptake uncovered in mammalians . because cells can transiently express ps during their activation , the two step model protects against accidental uptake ( henson et al . finally , clearance of apoptotic cells would suppress any potential autoimmmue responses directed toward self antigens through inhibition of monocyte and t cell activation and maturation of professional antigen - presenting cells like dendritic cells ( dcs ) . for instance , what is the role of receptors which potentially bind ps directly ( cd14 , scavenger receptors ) or through bridging molecules such as thrombospondin , lactadherin , ic3b , and 2glycoprotein i ? since psr expression may be a function of the activation status , geographic location and nature of the phagocyte ( absent on fresh monocytes but upregulated on activated macrophages [ fadok et al . , 2000 ] and present on immature dcs [ unpublished data ] ) , it remains to be established when this psr - dependent mechanism is dominant . is it only involved in the removal of acs during normal cell homeostasis , or does it also play a role in clearing cells generated during immune or inflammatory responses when responses must be subsequently downregulated ? defense collagens such as the collectins ( surfactant binding protein [ sp]-a ; mannose - binding lectin [ mbl ] ) and the complement component c1q , coat acs via their globular heads and initiate uptake by interacting with phagocyte receptors through their structurally homologous collagenous tail groups ( ogden et al . , 2001 ) . this interaction requires the recognition of tail groups by calreticulin ( cc1qr ) and cd91 . the latter is a receptor for 2macroglobulin and heat shock proteins in addition to calreticulin ( basu et al . , 2001 ) . importantly , defective ac clearance in c1q animals implicates this pathway in removal of dead cells under noninflammatory conditions ( taylor et al . , 2000 ) . the elegant ac surrogate model described here will be useful to address the hierarchical roles of recognition receptors in various circumstances and their relative dominance amongst professional and nonprofessional phagocytes . particles and cells may be internalized through receptor - mediated endocytosis , macropinocytosis , or phagocytosis . uptake via the tether and tickle mechanism occurs through macropinocytosis , since it is accompanied by membrane ruffling , formation of fluid filled phagosomes , and requires rac-1 and cdc42 , members of the rho family of gtpases that link cell surface receptors to actin cytoskeletal organization . a general role of these gtpases in ac uptake is supported by studies showing that murine bone marrow  derived macrophages are dependent on rac-1 , cdc42 , and wiskott - aldrich syndrome protein ( wasp ) . wasp is activated by cdc42 to stimulate actin polymerization through the arp2/3 complex ( leverrier et al . , 2001 ) . interestingly , immature dcs , which are constitutively macropinocytic and phagocytic , express activated cdc42 . as they mature , endocytic downregulation is accompanied by loss of activated cdc42 . in this context , one would predict that dcs would be less dependent on a  tickling  mechanism to internalize tethered particles . psr may associate with other surface molecules , since its intracellular tail composition provides few clues regarding uptake . association of calreticulin with cd91 after exposure to mbl or c1q - opsonized ac may induce aggregation and signaling via the latter 's tail , which contains two npxy endocytosis signal sequences ( gliemann et al . , 1994 ) . dock180 molecular complexes and triggers rac-1 , a process analogous to the homologous ced2ced5ced10 complex of engulfment genes defined in the nematode caenorhabditis elegans ( albert et al . , 2000 ) . the tyrosine protein kinases or phosphatidylinositol 3-kinases may link surface receptors to these downstream signaling molecules . how do these various signals translate into biological events associated with ac clearance ? rac-1 is an essential regulatory component of the nadph oxidase enzyme complex , and both rac and cdc42 activate the jnk and p38 mapk pathways . interestingly , these two molecular switches were found to be essential for fc gamma r  mediated uptake , which is associated with a respiratory burst and inflammatory responses in professional phagocytes ( caron and hall , 1998 ) . further biochemical and genetic analyses of the signaling pathways controlling ac uptake will lead to a better understanding of these fundamental processes . under noninflammatory conditions , uptake of acs by macrophages is thought to suppress autoimmune responses through production of il-10 , tgf , paf , and pge2 and inhibition of tnf , gm - csf , il-12 , il-1 , and il-8 release ( voll et al . , 1997 ; fadok et al . , ligation of psr has been proposed to be the primary mechanism through which these responses are initiated ( henson et al . , 2001a ) . under inflammatory conditions or in circumstances where ps or psr levels are reduced , henson et al . ( 2001b ) propose that other recognition systems dominate in clearance of dead cells ( e.g. , defense collagens ) and skew immune responses in a proinflammatory direction . however , this model of psr function as a molecular switch for immunity must take into account that ligation of other receptors can suppress autoimmune responses . blocks the release of proinflammatory cytokines upon stimulation with lipopolysaccharide . in addition , c1q mice which are defective in ac clearance , develop a syndrome resembling systemic lupus erythematosus ( taylor et al . , 2000 ) . it has been suggested that immature dcs promote tolerogenic responses through ligation of psr and cd36 ( henson et al . , 2001a ) . in some studies , this interaction has been shown to inhibit dc maturation and production of il-12 , while inducing il-10 ( urban et al . , 2001 ) . this is a point of contention , since others have failed to show inhibition of maturation or of inflammatory cytokine production upon ac uptake ( sauter et al . , 2000 ) . furthermore , it is clear that immature dcs phagocytose multiple sources of acs ( including bacteria- or virus - infected cells and cancer cells ) and upon maturation ( i.e. , process and present ) antigens from these sources and activate cd4 and cd8 t cells ( albert et al . , 1998 ) . studies of receptor recognition systems have shed light on how antigen - presenting cells react to different types of dead cells . exposure of macrophages and dcs to necrotic cells ( ncs ) induces their activation , likely via heat shock proteins and calreticulin within cell lysates . interestingly , through binding to cd91 these same proteins promote cross presentation of chaperoned antigenic peptides ( basu et al . , 2001 ) . since defense collagens bridge ac to macrophages via calreticulin and cd91 ( ogden et al . , 2001 ) , nc and c1q , spa , or mbl - opsonized ac may share a common receptor for their uptake ( chung et al . , 2000 ) . this pathway could account for the ability of dcs to crosspresent antigens from ac and nc . indeed , a common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in the nematode ( chung et al . , 2000 ) . further studies of dead cell receptor recognition proteins will lead to a better understanding of how immunity can be modulated to minimize autoimmune responses while maximizing the host response against infection .
several receptors are implicated in apoptotic cell ( ac ) uptake by phagocytic cells ; however , their relative dominance in mammalian systems remains to be established . 
 new studies shed light on the role of the phosphatidyl serine ( ps ) receptor ( psr ) . 
 ligation of psr by ps on ac surfaces is considered essential for signaling uptake of acs that are tethered to phagocytes via other receptors .