RPTPϵ promotes M2-polarized macrophage migration through ROCKII signaling and podosome formation.

Cysteinyl-leukotrienes (cys-LTs) have well-characterized physiopathological roles in the development of inflammatory diseases. We have found that protein tyrosine phosphatase epsilon (PTPϵ) is a signaling partner of CysLT1R, a high affinity receptor for leukotriene D4 (LTD4). There are two major isoforms of PTPϵ, receptor-like (RPTPϵ) and cytoplasmic (cyt-)PTPϵ, and in most cells, their expression is mutually exclusive, except in human primary monocytes, which express both isoforms. Here we show differential PTPϵ isoform expression patterns between monocytes, M1 and M2 human monocyte-derived macrophages (hMDM) with the expression of glycosylated forms of RPTPϵ predominantly in M2-polarized hMDMs. Using PTPϵ-specific siRNAs and expression of RPTPϵ and cyt-PTPϵ, we found that RPTPϵ was involved in monocyte adhesion and migration of M2-polarized hMDMs in response to LTD4. Altered organization of podosomes and higher phosphorylation of the inhibitory Y-722 residue of ROCKII was also found in PTPϵ-siRNA-transfected cells. In conclusion, we show that differentiation and polarization of monocytes into M2-polarized hMDMs modulates the expression of PTPϵ isoforms and RPTPϵ is involved in podosome distribution, ROCKII activation and migration in response to LTD4.