A regulatory role for macrophage class A scavenger receptors in TLR4-mediated LPS responses.
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 up-regulation 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.
Chen
Yunying
Y
Department of Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden. yunying.chen@ki.se
Wermeling
Fredrik
F
Sundqvist
Johanna
J
Jonsson
Ann-Beth
AB
Tryggvason
Karl
K
Pikkarainen
Timo
T
Karlsson
Mikael C I
MC
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D012333:RNA, Messenger / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D015854:Up-Regulation
D016207:Cytokines; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; C092228:Marco protein, mouse; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016753:Interleukin-10