Researchers from Children’s Hospitaland Institutes of Biomedical Sciencesof Fudan University revealed the molecular mechanisms underlying macrophage subset activation, which could assist in the diagnosis and treatment of human inflammatory diseases, in their paper titled “LncRNA PTPRE-AS1 modulates M2 macrophage activation and inflammatory diseases by epigenetic promotion of PTPRE”, published in Science Advances on December 11.
As the importantcomponents of innate immunity and regulators of inflammatoryresponses, macrophages are divided into functionally distinct forms, including classically activated (M1) subset and alternatively activated (M2) subset. M1 macrophages, activated by LPS and IFN-γ and inducing responses from Th1 cells, contribute to inflammatory immune responses. M2 macrophages, activated by IL-4, IL-13 and IL-10 and inducing responses from Th2 cells, are associated with allergic asthma. However, the roles of long noncoding RNAs (lncRNAs) in M2 macrophages activation are largely unknown.
The researchers found that lncRNA PTPRE-AS1was selectively expressed in IL-4–stimulated M2 macrophages. Knockdown of PTPRE-AS1 in RAW 264.7 cells and bone marrow–derived macrophages led to significantly elevated levels of M2-associated gene expression, specifically the expression of IL-10 and CD206. In addition, overexpression of PTPRE-AS1 inhibited the activation of M2 macrophages.
PTPRE-AS1 exerted cis-regulatoryeffects on nearby PTPRE genes. PTPRE, aprotein tyrosine phosphatase, was involved in the negative regulation of the mitogen-activatedprotein kinase (MAPK)/extracellular signal–regulated kinase (ERK) 1/2 pathways, influencing M2-associated gene expression. Using a combination of nuclear localization, RIP assays and RNA pull-down assays, researchers discovered that mechanistically, PTPRE-AS1 bound WDR5 directly, modulating H3K4me3 of the PTPRE promoter region to activate PTPRE transcription.
They generated PTPRE-AS1 KO mice and noted much higher levels of M2-associated gene in colon tissues from DSS-treated PTPRE-AS1-deficient mice than DSS-treated WT mice, thereby preventing colitis development. But in the mouse model of cockroach extract (CRE) allergen–induced pulmonary allergic inflammation, the excessive activation of M2 macrophages exacerbated lung inflammation. By evaluating the expression of PTPRE-AS1 and PTPRE in PBMCs from children with allergic asthma and healthy control subjects, elevated levels of M2-associated genes, including IL-10 and CD206, were detected in patients with asthma, while a negative correlation between PTPRE-AS1 and CD206 was identified.
The research revealed PTPRE-AS1 controlled M2 macrophage activation through epigenetic up-regulation of PTPRE expression by binding to WDR5, leading to chromatin remodeling and the regulation of PTPRE-dependent signaling during M2 macrophage activation and the development of inflammatory diseases such as allergic asthma and inflammatory bowel diseases.
Xiao Han, Saihua Huang, Ping Xue and Jinrong Fu are the first authors, with researcher Yufeng Zhou being the corresponding author.
Full text link：https://advances.sciencemag.org/content/5/12/eaax9230