Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Classical signaling lymphocyte activating molecule (SLAM) family receptors are abundant within many types of immune cells, whereas the nonclassical SLAM family receptors SLAMF8 and SLAMF9, which uniquely lack cytoplasmic signaling motifs, are highly expressed by myeloid cells. Due to the potential redundancy, whether these two receptors regulate macrophage function remains largely unknown. Here, we show that SLAMF8 and SLAMF9 co-regulate macrophage-mediated liver inflammation. To overcome the redundancy, we generated mice that simultaneously lacked SLAMF8 and SLAMF9 using CRISPR-Cas9 technology. Although macrophage differentiation was not altered by the combined deficiency of SLAMF8 and SLAMF9, the loss of these two receptors significantly protected against lipopolysaccharide (LPS)-induced liver injury. SLAMF8 and SLAMF9 double-deficient mice had a prolonged survival rate and less infiltration of inflammatory cells. The depletion of macrophages using clodronate liposomes abolished the effects of SLAMF8 and SLAMF9 deficiencies on LPS-induced liver injury, which demonstrates that these receptors are required for macrophage activation following LPS challenge. Moreover, the deficiency of SLAMF8 and SLAMF9 suppressed the secretion of inflammatory cytokines by downregulating the expression of Toll-like receptor-4 (TLR4), a receptor that specifically binds LPS, which led to decreased mitogen-activated protein kinases (MAPK) signaling activation. Notably, combined injections of truncated extracellular SLAMF8 and SLAMF9 proteins significantly alleviated LPS-induced liver injury. Thus, our findings provide insights into the role of SLAMF8 and SLAMF9 in endotoxin-induced liver injury and suggest that SLAMF8 and SLAMF9 are potential therapeutic targets for acute hepatic injury.
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PMID:Combined deficiency of SLAMF8 and SLAMF9 prevents endotoxin-induced liver inflammation by downregulating TLR4 expression on macrophages. 3055 82