Lgr4/Gpr48 Negatively Regulates TLR2/4-associated Pattern Recognition and Innate Immunity by Targeting CD14 Expression

The recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is pivotal in both innate and adaptive immune responses. Here we demonstrate that deletion of Lgr4/Gpr48 (G-protein-coupled receptor 48), a seven-transmembrane glycoprotein hormone receptor, potentiates TLR2/4-associated cytokine production and attenuates mouse resistance to septic shock. The expression of CD14, a co-receptor for TLR2/4-associated pathogen-associated molecular patterns, is increased significantly in Lgr4-deficient macrophages, which is consistent with the increased immune response, whereas the binding activity of cAMP-response element-binding protein is decreased significantly in Lgr4-deficient macrophages, which up-regulate the expression of CD14 at the transcriptional level. Together, our data demonstrate that Lgr4/Gpr48 plays a critical role in modulating the TLR2/4 signaling pathway and represents a useful therapeutic approach of targeting Lgr4/Gpr48 in TLR2/4-associated septic shock and autoimmune diseases. Background: Lgr4/Gpr48 has been found to play an important role in development of different organs. Results: Overactivated innate immune response was found in Lgr4-deficient mice. Conclusion: Lgr4/Gpr48 could be a negative regulator in TLR2/4-associated immune responses. Significance: Our novel findings provide new insights into the physiological functions of Lgr4/Gpr48 in immune diseases.