KLF Transcription Factor 5/Lysophosphatidic Acid Receptor 5 Induced M2 Macrophage Activation and Inflammation by Modulating Phosphorylation of Mitogen-Activated Protein Kinase Kinase Kinase 7 in Pediatric Asthma

Pediatric asthma is a respiratory disease in which M2 macrophages play a critical role. Here, the role and molecular mechanism of lysophosphatidic acid receptor 5 (LPAR5) were investigated in pediatric asthma through in vivo and in vitro experiments. LPAR5 expression was increased in peripheral blood mononuclear cells from children with asthma. In an ovalbumin-induced neonatal asthmatic mouse model, LPAR5 Antagonist alleviated airway inflammation by suppressing the release of inflammatory cytokines and inflammatory cell infiltration. Ovalbumin-induced M2 macrophage activation in neonatal mouse lung tissue was suppressed by LPAR5 Antagonist, accompanied by decreased YM1 protein (encoded by chitinase 3 like 1) secretion. Differentiated THP-1 cells were stimulated with IL-4 to mimic M2 macrophages in vitro. M2 macrophage activation was reduced by both LPAR5 Antagonist or LPAR5 knockdown. Furthermore, KLF transcription factor 5 (KLF5) was significantly up-regulated and positively correlated with LPAR5 expression in peripheral blood mononuclear cells from children with asthma. KLF5 bound to the promoter of LPAR5 and transcriptionally promoted LPAR5 expression. LPAR5 overexpression increased M2 macrophage activation in KLF5-depleted THP-1 cells. The underlying mechanism of LPAR5 was investigated by phosphorylomics analysis, which identified mitogen-activated protein kinase kinase kinase 7 as a possible downstream effector. The results showed that LPAR5 Antagonist attenuated airway inflammation in neonatal mice by decreasing M2 macrophage activation. KLF5 positively regulates the expression of LPAR5, which further increased the phosphorylation of mitogen-activated protein kinase kinase kinase 7 protein in macrophages. This article highlights that LPAR5 might serve as a potential target in pediatric asthma.