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Address correspondence to Nina Bhardwaj, The Laboratory of Molecular Neuro-Oncology, The Rockefeller University, Room 41, Box #176, 1230 York Ave., New York, NY 10021. Tel.: (212) 327-8332. Fax: (212) 327-7232. E-mail bhardwn{at}mail.rockefeller.edu
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Abstract |
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Contribution of phosphatidylserine receptor to apoptotic cell uptake |
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New paradigms generate a host of new questions. 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 ß2glycoprotein I? Do they simply provide tethering signals or do they deliver both signals? 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(absent on fresh monocytes but upregulated on activated macrophages [Fadok et al., 2000] and present on immature DCs [unpublished data]), it remains to be established when this PSR-dependent mechanism is dominant.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?
PSR-independent pathways clearly exist (Fig. 1). 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.
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Signaling mechanisms in apoptotic cell uptake |
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The signaling mechanisms that link AC receptors to the GTPases remain to be defined. 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). Signaling through the integrin vß5 on nonprofessional phagocytes recruits p130casCrkIIDock180 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 Rmediated uptake, which is associated with a respiratory burst and inflammatory responses in professional phagocytes (Caron and Hall, 1998). Presumably, the nature of the initial recognition receptor influences the subsequent responses. Further biochemical and genetic analyses of the signaling pathways controlling AC uptake will lead to a better understanding of these fundamental processes.
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Modulation of the immune response |
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Uptake of ACs by DCs is also significant to the immune response. 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 "cross present" (i.e., process and present) antigens from these sources and activate CD4+ and CD8+ T cells (Albert et al., 1998). DCs use vß5 preferentially to
vß3 as an AC receptor. This difference may explain the disparity in fates of ACs in DCs versus macrophages.
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.
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Footnotes |
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References |
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