Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

Abstract

Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Tolllike receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor kB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-a, interleukin-1b, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Merneutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury.

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

“…MerTK engagement triggers AC internalization via cytoskeletal signaling, and it also activates an anti-inflammatory response by suppressing NF-κB (15,16). As such, MerTK knockout mice develop a lupus-like phenotype in aged mice (17), demonstrate accelerated atherosclerosis in hypercholesterolemic mice due to defective clearance of ACs and heightened inflammation (18,19), and have increased peritonitis in response to a sterile inflammatory stimulus (20).…”

Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution

“…This hypothesis is supported by previous studies showing that MerTK loss from the mammary gland during physiological postpartum involution reduces efferocytosis of dying MECs, causing impaired upregulation of Il10 and Tgfb1 (30). Other studies demonstrated that MerTK-mediated efferocytosis of dying neutrophils or injured cardiomyocytes, liver cells, or lung epithelial cells induces the transcription of wound-healing cytokines that promote resolution of acute inflammation and tissue repair (47,50,54,(58)(59)(60)(61)(62). While MerTK-mediated efferocytosis is desirable in physiological (e.g., postpartum involution of the breast) or pathological (e.g., tissue damage) wound-healing situations, our results suggest that efferocytosis-mediated tissue repair in tumors would enhance tumor metastasis.…”

The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

“…Although advances in supportive care and ventilator management for human ARDS have reduced short-term mortality [2], effective pharmacological therapies are still lacking. In this context, recent studies evaluated the role of tyrosine kinase inhibitors in experimental ARDS [3][4][5]. As major therapeutic agents in oncology, these pharmacological agents block the action of different classes of protein tyrosine kinases (PTKs), important molecules that regulate many intracellular signaling pathways, including the acute inflammatory response to different stimuli [6].…”