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

Abstract

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 à 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...

Wnt1 Participates in Inflammation Induced by Lipopolysaccharide Through Upregulating Scavenger Receptor A and NF-kB

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Cutting Edge: Marginal Zone Macrophages Regulate Antigen Transport by B Cells to the Follicle in the Spleen via CD21

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