Induced Pluripotent Stem Cells Regulate Triggering Receptor Expressed on Myeloid Cell-1 Expression and the p38 Mitogen-Activated Protein Kinase Pathway in Endotoxin-Induced Acute Lung Injury.

Abstract

Induced pluripotent stem cells (iPSCs) can attenuate the pathological severity and neutrophil migration of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, interactions that may occur between iPSCs and the triggering receptor expressed on myeloid cells (TREM) family of proteins remain unclear. In this study, murine iPSCs (miPSCs) were delivered via tail vein injection to wild type, TREM-1 knockout (KO), and TREM-2 KO C57BL/6 mice 4 hours after an intratracheal delivery of LPS. Twenty-four hours later, the bronchoalveolar lavage fluid and lung tissue were collected to perform histology, immunohistochemistry, neutrophil counts, Western blot assays, and enzyme-linked immunosorbent assays. Neutrophils were also isolated from the bone marrow to perform in vitro migration assays. In the lung tissues collected, LPS increased the expression of TREM-1 and TREM-2, with the TREM-2 KO mice expressing more TREM-1 than the wild-type mice. The TREM-2 KO mice also exhibited greater severity of LPS-induced ALI, enhanced neutrophil infiltration in the lung tissues, and a higher ratio of phosphorylated p38 to total p38 (p-p38/p38) in neutrophils. The p-p38/p38 ratio and the expression of vascular cell adhesion molecule-1 and certain proinflammatory cytokines (macrophage inflammatory protein-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β) were increased in whole lung extracts following LPS-induced ALI, and these levels were even more in LPS-treated TREM-2 KO mice. These effects were reduced when miPSCs were administered. Thus, the results of this study suggest that miPSCs attenuate the role of neutrophils in lung inflammation and injury induced by LPS by reducing their expression of TREM-1 and p38 mitogen-activated protein kinase signaling. Stem Cells 2019;37:631-639.