MARCO, an innate activation marker of macrophages, is a class A scavenger receptor for <i>Neisseria meningitidis</i>

Mukhopadhyay, Subhankar; Chen, Yunying; Sankala, Marko; Peiser, Leanne; Pikkarainen, Timo; Kraal, Georg; Tryggvason, Karl; Gordon, Siamon

doi:10.1002/eji.200535389

Cited by 80 publications

(78 citation statements)

References 34 publications

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“…Both receptors can interact with the major Gram-negative cell wall component LPS, 11,12 but such interaction is not essential for SR-A/MARCO-mediated uptake of Gramnegative organisms. 26,27 Similarly, TLR4 rather than SR-A and MARCO is required for LPS-mediated inflammatory responses. While LPS-independent ligands have been implicated in SR-A/ MARCO-mediated uptake, the significance of SR-A/MARCOmediated LPS recognition is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…27 Four days after injection, cells were harvested by peritoneal lavage with ice-cold PBS and plated on bacteriological plastic dishes in a defined serum-free medium, OPTIMEM-1, supplemented with 500 IU/mL of penicillin-streptomycin and 2mM glutamine. After 3-4 hours, plates were washed 3 times to remove nonadherent cells and Biogel beads.…”

Section: Isolation and Culture Of Primary Mmentioning

confidence: 99%

“…SR-A and MARCO are 2 major nonopsonic phagocytic receptors for NM, but such recognition is independent of neisserial LPS. 26,27 In contrast, NM-mediated cytokine responses depend on TLR4-mediated recognition of NM LPS and do not require SR-A/ MARCO-mediated NM uptake. 26 We utilized polyinosinic acid (polyI) a synthetic polyanionic ligand for SR-A/MARCO that also stimulates intracellular TLR3 to release inflammatory cytokines.…”

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confidence: 99%

“…26,27 We previously reported that although Bg-PM and resident peritoneal macrophages (RPMs) from SR-A Ϫ/Ϫ and DKO mice are significantly deficient in NM uptake, they showed a modest increase in TNF-␣ secretion. 27 In the present study, we set out to compare how SR-A and MARCO contribute to NM clearance and modulate early cytokine responses in vivo. WT, SR-A Ϫ/Ϫ , MARCO Ϫ/Ϫ , and DKO mice were injected intraperitoneally with fluorescently labeled NM, peritoneal exudate cells were isolated after 45 minutes, and NM uptake was measured by flow cytometry.…”

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confidence: 99%

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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

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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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Section: Discussionmentioning

confidence: 99%

Section: Isolation and Culture Of Primary Mmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

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110

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“…First, the mice were challenged i.p. with Neisseria meningitidis (NM), a gramnegative bacterium shown to be recognized by SR-A and MARCO [8,20]. CFU in blood of WT and DKO mice were measured at days 1, 2, 3 and 7 after the injection.…”

Section: Sr-deficient Mice Are Defective In the Bacterial Clearance Imentioning

confidence: 99%

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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Macrophage Function Disorders

Lee¹,

Yin²,

Bowdish³

2013

Encyclopedia of Life Sciences

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Macrophages are sentinel cells of the innate immune response. Macrophages recognise pathogen‐associated molecular patterns (e.g. microbial products) and endogenous ligands (e.g. apoptotic cells) through a broad and adaptable range of pattern‐recognition receptors. The consequence of this recognition is generally effective clearance via phagocytosis; however, when this is not effective, macrophages may become inappropriately activated and initiate an inappropriate inflammatory response. Because macrophages are extremely variable in phenotype and function and share a common ancestry with monocytes and dendritic cells, there are very few genes that are expressed exclusively in macrophages. Consequently, macrophage‐specific immunodeficiencies are rare. There are, however, a number of genetic immunodeficiencies that affect macrophage function. In addition, as macrophages are exquisitely attuned to their microenvironment, their function appears to be adversely affected by and contributes to chronic inflammatory conditions such as cancer, atherosclerosis and obesity. Thus, genetic deficiencies, in addition to microenvironmental dysregulation, can contribute to macrophage function disorders. Key Concepts: Macrophages functions include sensing of modified host proteins, microbes and microbial components. Macrophages respond to these ligands primarily through phagocytic and inflammatory receptors. Macrophage function is exquisitely attuned to the microenvironment and when chronic inflammatory conditions alter the microenvironment, macrophage function can become impaired. Primary immunodeficiencies have been identified that impair macrophage phagocytosis and inflammatory responses and leave the patient susceptible to infectious disease and other chronic conditions. Macrophages are able to sense a wide and diverse variety of endogenous and exogenous ligands, including modified host proteins, microbes, and microbial components. Chronic inflammatory conditions such as cancer and atherosclerosis alter the microenvironment, which can impair the ability of macrophages to maintain homeostasis.

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MARCO, an innate activation marker of macrophages, is a class A scavenger receptor for Neisseria meningitidis

Cited by 80 publications

References 34 publications

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

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

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

Macrophage Function Disorders

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