Role of macrophage scavenger receptor in endotoxin shock

Kobayashi, Yoshito; Miyaji, Chikako; Watanabe, Hirotaka; Umezu, Hajime; Hasegawa, Go; Abo, Toru; Arakawa, Masaaki; Kamata, Norio; Suzuki, Hiroshi; Kodama, Tatsuhiko; Naito, Makoto

doi:10.1002/1096-9896(2000)9999:9999<::aid-path692>3.0.co;2-u

Cited by 61 publications

(26 citation statements)

References 38 publications

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“…SR-A in LPS responses have yielded different outcomes, probably due to different challenging protocols [36,37]. The SR-A À/À mice were not included in our study, but the phenotypes were always more severe in the DKO mice than in those lacking MARCO only, indicating a functional role for both receptors.…”

Section: Discussionmentioning

confidence: 98%

“…Further, the conclusion that class A SR contribute to the microbial clearance upon infection is also supported by the findings in a study in which WT and SR-A À/À mice were challenged with Staphylococcus aureus [35]. However, the studies addressing the role of SR-A in LPS responses have yielded different outcomes, probably due to different challenging protocols [36,37]. The SR-A À/À mice were not included in our study, but the phenotypes were always more severe in the DKO mice than in those lacking MARCO only, indicating a functional role for both receptors.…”

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confidence: 79%

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A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

et al. 2010

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Recognition of microbial components by TLR, key sensors of infection, leads to induction of inflammatory responses. We found that, in vivo, TLR4 engagement by LPS induces upregulation of the class A scavenger receptors (SR) macrophage receptor with a collagenous structure (MARCO) and SR-A, which occurs, at least in the case of MARCO, via both MyD88-dependent and -independent pathways. When challenging mice with a low dose of LPS followed by a high dose, class A SR-deficient mice showed a higher survival rate than WT mice. This was paired with increased production of IL-10 and anti-LPS Ab, as well as increased activation status of marginal zone B cells. However, the receptors were not crucial for survival when challenging mice i.p. with Neisseria meningitidis or Listeria monocytogenes, but they were found to contribute to microbial capture and clearance. This indicates physiological significance for the up-regulation of class A SR during early stages of bacterial infection. Thus, we believe that we have revealed a mechanism where SR regulate the activation status of the immune system and are involved in balancing a proper immune response to infection. This regulation could also be important in maintaining tolerance since these receptors have been shown to be involved in regulation of self-reactivity.Key words: Class A scavenger receptors . KO mice . LPS response . Spleen marginal zone B cells IntroductionLPS is a cell wall component of gram-negative bacteria, recognized, amongst others, by the TLR4/MD2 signalling receptor complex. Animals that have mutations in MD2 or TLR4 are susceptible to gram-negative bacterial infection due to the failure to sense LPS [1,2]. However, when animals sense LPS and respond too vigorously, they may be the victims of their own inflammatory overreaction. Therefore, the outcome of bacterial infection is determined not only by the ability to sense endotoxin, but also by mechanisms limiting the inflammatory response. Accordingly, mammals are equipped with many LPS detoxification mechanisms preventing vigorous inflammation [3]. For example, soluble proteins, such as natural Ab-binding LPS, prevent it from engaging the TLR4/MD2-complex and protect animals from endotoxin challenge [4,5]. Further, LPS can be Ã These authors contributed equally to this work. Class A SR MARCO (macrophage receptor with a collagenous structure) and SR-A (scavenger receptor A) have a potential for this type of regulation, since their ligand repertoire includes LPS and they are expressed by macrophages that respond quickly to infection. MARCO has a restricted expression pattern being expressed on specific macrophage subsets in spleen marginal zone (MZ), lymph nodes and peritoneum, whereas SR-A is more widely expressed. In vitro studies have shown that the expression of both receptors can be up-regulated in a TLR-dependent manner, suggesting that they might play a regulatory role in TLRmediated innate immune response [7,8].Being expressed primarily on MZ macrophages in the naïve spleen, MARCO and SR-A are in clos...

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Section: Discussionmentioning

confidence: 98%

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confidence: 79%

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

et al. 2010

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“…For example, macrophage death induced by combinatorial PRR signaling may be a host defense mechanism against those pathogenic organisms that seek safe haven inside living macrophages (36)(37)(38). With regard to evidence that SRA and TLR4 may functionally interact in vivo, three independent reports have shown that mice lacking SRA have altered cytokine and survival responses to LPS (39)(40)(41), although the mechanisms of the altered responses were not elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, IRF3 also can function as a coactivator of NF-B-regulated genes (50), and so inhibition of IRF3 by SRA might prevent activation of genes involved in the inflammatory response. This hypothesis may provide insight into how SRA affects the inflammatory response to LPS in vivo (39)(40)(41). Addressing these questions and probing combinatorial PRR apoptosis signaling in vivo may yield new therapeutic strategies related to diseases and host defense processes in which the balance between macrophage survival and death plays important roles.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon

Obstfeld²,

Moore³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

166

194

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Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Tolllike receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-␤ branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-␤, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-␤. Thus, combinatorial signaling between two distinct PRRs results in a functional outcomemacrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.apoptosis ͉ atherosclerosis ͉ scavenger receptor ͉ Toll-like receptor ͉ innate immunity

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“…20 Our current finding that SR-A Ϫ/Ϫ , MARCO Ϫ/Ϫ , and DKO mice showed defective bacterial clearance but produced higher levels of inflammatory cytokines after intraperitoneal NM challenge is consistent with most previous reports 11,36 ; although enhancement of LPS responses has also been reported. 37 Apart from the secretion of bioactive mediators, another hallmark of inflammation is the infiltration of specific leukocyte populations into affected tissue. This process is regulated by a series of complex changes in damaged tissue, vascular endothelia, and migrating leukocytes.…”

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confidence: 99%

SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens

Mukhopadhyay

Varin

Chen

et al. 2011

Blood

110

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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...

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Role of macrophage scavenger receptor in endotoxin shock

Cited by 61 publications

References 38 publications

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

A regulatory role for macrophage class A scavenger receptors in TLR4‐mediated LPS responses

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens

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