Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-κB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury

Mer as an intrinsic feedback inhibitor of the TLR4‐driven immune responses during acute lung injury. Mer signaling participates in a novel inhibitory pathway in TLR activation. The purpose of the present study was to examine the role of Mer signaling in the down‐regulation of TLR4 activation‐driven immune responses in mice, i.t.‐treated with LPS, using the specific Mer‐blocking antibody. At 4 h and 24 h after LPS treatment, expression of Mer protein in alveolar macrophages and lung tissue decreased, sMer in BALF increased significantly, and Mer activation increased. Pretreatment with anti‐Mer antibody did not influence the protein levels of Mer and sMer levels. Anti‐Mer antibody significantly reduced LPS‐induced Mer activation, phosphorylation of Akt and FAK, STAT1 activation, and expression of SOCS1 and ‐3. Anti‐Mer antibody enhanced LPS‐induced inflammatory responses, including activation of the NF‐κB pathway; the production of TNF‐α, IL‐1β, and MIP‐2 and MMP‐9 activity; and accumulation of inflammatory cells and the total protein levels in BALF. These results indicate that Mer plays as an intrinsic feedback inhibitor of the TLR4‐ and inflammatory mediator‐driven immune responses during acute lung injury.