Marginal zone macrophages (MZMs) are a small subset of specialized splenic macrophages known to interact with apoptotic material entering the spleen from circulation. To evaluate whether MZMs regulate immunity to apoptotic material we depleted MZMs and assessed innate and adaptive immune responses to apoptotic cells administered systemically. MZM depletion altered the spatial localization of apoptotic cells, which accumulated in T-cell areas of the lymphoid follicles. MZM depletion also enhanced phagocytosis of apoptotic cells by red pulp (CD68 ؉ F4/80 ؉ ) macrophages, which expressed increased CD86, MHCII, and CCR7. MZM depletion led to increased production of proinflammatory cytokines and enhanced lymphocyte responsiveness to apoptotic cell antigens. Furthermore, we found that MZM depletion accelerated autoimmune disease progression in mice genetically prone to systemic lupus erythematosus and caused significant mortality in wild-type mice repeatedly exposed to exogenous apoptotic thymocytes. These IntroductionThe marginal zone (MZ) of the spleen represents the boundary between the lymphoid white pulp (WP) and the more innate scavenging red pulp (RP). 1 Most arterial blood entering the spleen passes through the MZ where it interacts with nonmotile macrophages tightly bound to the reticulum. 2,3 These macrophages line the marginal sinus and are defined by differential expression of macrophage scavenger receptor MAcrophage Receptor with a COllagenous structure (MARCO).The MZ is essential for trapping of particulate antigen, and MZ macrophages (MZMs) in particular have been implicated in this function. 4 MARCO ϩ macrophages are well equipped for this because they express an array of scavenger receptors in addition to MARCO, including scavenger receptor A (SR-A) and SIGNR1 (a mouse homologue of DC-SIGN). Moreover, MARCO ϩ macrophages are thought to be essential in the response to several blood-borne pathogens, 4-7 and studies have indicated mice deficient in MZMs are more susceptible to infection with altered T-cell response to antigenic challenge. 4,6 The importance of MZMs in the clearance of endogenous material is less clear. SR-A and MARCO bind to acetylated and oxidized low-density lipoprotein and polyanionic ligands. 8,9 Moreover, both scavenger receptors aid in capture and phagocytosis of apoptotic cells by macrophages in vitro, suggesting an involvement in MZ-mediated retention of apoptotic material. 10,11 Curiously, deletion of either receptor has no apparent effect on apoptotic cell clearance in vivo, 12 probably reflecting mechanistic redundancy. However, we have demonstrated that apoptotic cell injection in SR-A/MARCO double knockout (KO) mice led to increased production of anti-dsDNA antibodies whereas injection in wild-type, SR-A, or MARCO single KO mice had no effect. 11 Further, in murine lupus MARCO expression is associated with defects in apoptotic cell phagocytosis and autoimmunity. 13 Systemic apoptotic cell administration leads to suppression of immune responsiveness to apoptotic cell-associa...

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell–derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.

Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A IntroductionInnate immune recognition of microbes by pattern recognition receptors (PRRs) initiates 2 distinct effector responses, phagocytosis and inflammation, to promote pathogen clearance, killing, tissue repair, and induction of adaptive immunity. 1 Phagocytic PRRs, such as scavenger receptors, and pathogen sensors, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), mediate uptake and initiate inflammation, respectively. 2,3 Although much has been learned about these 2 processes separately, knowledge is still limited on how these processes are coordinated during the host response. Functional collaboration between innate receptor families must exist to coordinate uptake and inflammation; breakdown in such receptor collaboration can lead to defective pathogen clearance and inflammatory pathologies. 4 The scavenger receptor A (SR-A) and macrophage receptor with collagenous structure (MARCO) are 2 well-characterized, nonopsonic phagocytic receptors on myeloid cells. 5,6 Due to their shared multidomain structure and their ability to bind modified low-density lipoprotein and other polyanionic ligands (a common feature of all scavenger receptors), they are defined as members of the class-A scavenger receptor family. Both molecules are multiligand, multifunctional receptors 7 ; share large numbers of overlapping but distinct polyanionic ligands; and carry out common functions such as cellular adhesion, 8 migration, 9 phagocytosis, and antigen presentation. 10 Both receptors have been shown to bind a range of isolated microbial components 11-14 and intact Grampositive and Gram-negative organisms, 15,16 and their nonredundant role in host defense has been established in a variety of bacterial infection models. [17][18][19][20] Although SR-A and MARCO recognize a range of highly inflammatory ligands, these receptors by themselves are unable to initiate inflammatory signaling, which is usually triggered by sensing PRRs that share overlapping ligand repertoires. However, SR-A and MARCO have been implicated in the pathogenesis of a range of chronic and acute inflammatory pathologies, including atherosclerosis, Alzheimer disease, granuloma formation, and septic shock. 21 Studies utilizing both microbial and sterile inflammatory stimuli and distinct models of inflammation have suggested both proinflammatory and anti-inflammatory roles; however, the mechanisms for such apparent discrepancies are unknown. Therefore, how SR-A...

The scavenger receptor-A I/II (SR-A) and macrophage receptor with collagenous domain (MARCO) share a common domain organisation and ligand repertoire, including selected polyanions and gram-positive and -negative organisms, but differ in fine specificity of ligand binding, tissue distribution and regulation. Neisseria meningitidis (NM) is a selective ligand for SR-A, but there is evidence for an additional SR-A-independent, polyanion-sensitive component for NM recognition. We therefore studied the relative contribution of MARCO and SR-A to binding of NM by resident and elicited peritoneal macrophages obtained from MARCO -/-, SR-A -/-and SR-A-MARCO -/-mice. Results confirmed that both mouse and human MARCO are able to bind NM independently of NM LPS. MARCO and SR-A contributed independently to NM binding, correlating with their expression levels in different cell populations, but neither of these two molecules was required for release of TNF-a and nitric oxide. We propose that the TLR-dependent induction of MARCO by innate immune stimulation enhances recognition and uptake of pathogenic organisms such as NM, thus contributing to host defence against infection. IntroductionScavenger receptors (SR) are a family of structurally unrelated receptor proteins functionally defined by their ability to recognise modified low-density lipoprotein [1,2]. Although a large body of research has been directed to identify the role of SR in atherosclerosis, the description of SR as microbial pattern recognition receptors has only recently been appreciated. SR-A(I/ II) [2], the first member of the class-A SR family to be cloned, is a trimeric myeloid-restricted cell surface glycoprotein, able to recognise multiple ligands and perform varied cellular functions. Eur. J. Immunol. 2006. 36: 940-949

The macrophage scavenger receptor macrophage receptor with a collagenous structure (MARCO) is expressed in mice by the marginal zone macrophages of the spleen and by macrophages of the medullary cords of lymph nodes, as well as the peritoneal macrophages. MARCO is a relative of scavenger receptor A (SR-A), the more widely expressed prototypic member of the scavenger receptor family. In the present study, we found that genetic ablation of MARCO leads to changes in the organization of the splenic marginal zone, and causes a significant reduction in the size of the resident peritoneal macrophage population, possibly due to changes in adhesion and migration capacity. In mice lacking both MARCO and SR-A these effects are even more apparent. During ontogeny, the appearance and organization of the MARCO-expressing cells in the spleen precedes the appearance of other receptors on macrophages in the marginal zone, such as SIGNR1 and Siglec-1. In the absence of MARCO, a clear delay in the organization of the marginal zone was observed. Similar findings were seen when the reappearance of the various subsets from precursors was studied after depleting macrophages from the adult spleen by a liposome treatment. When challenged with a pneumococcal polysaccharide vaccine, a T-independent type 2 Ag for which an intact marginal zone is crucial, the knockout mice exhibited a clearly impaired response. These findings suggest that both MARCO and SR-A, in addition to being important scavenger receptors, could be involved in the positioning and differentiation of macrophages, possibly through interaction with endogenous ligands.