PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium–Induced Colitis

Abstract

PTPN22, a protein tyrosine phosphatase expressed mainly in hematopoietic cells, has been linked to many autoimmune diseases. A C-to-T single nucleotide polymorphism (SNP) at position 1858 of human PTPN22 cDNA decreases the risk of Crohn’s disease. However, the function of PTPN22 and the mechanism by which this SNP reduces the risk of Crohn’s disease are poorly understood. We find that PTPN22 is expressed in macrophages. It suppresses M1 macrophage polarization and reciprocally promotes the expression of M2-associated genes. PTPN22-deficient mice develop severe colitis induced by dextran sulfate sodium, and their intestinal macrophages express higher levels of M1 genes but lower levels of M2-associated genes. Furthermore, the protective T allele of the C1858T SNP is associated with attenuated expression of inflammatory cytokines and a higher level of PTPN22 in human M1 macrophages. This T allele–associated aberrant expression of PTPN22 is partly attributed to an autoinhibition mechanism, in which PTPN22 suppresses its own expression in M1 but not M2 macrophages. Our data not only demonstrate a critical role of PTPN22 in regulating macrophage polarization but also provide a molecular explanation for the protective effect of the C1858T SNP in Crohn’s disease.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…However, the impaired expression of ATM and PFKFB3, which are also induced by anti-CD3 stimulation, in ARI PBMCs cannot be explained by stronger activation signals and suggests a novel mechanism. The phosphatase activity of PTPN22 also inhibits the signals induced by type I interferon (49), modulates macrophage polarization (50), and activates the inflammasome by dephosphorylating NLRP3 (51). A role of NLRP3 in Th cells was recently discovered (52).…”

Phosphatase regulation of macrophage activation

“…In contrast to the previously described phosphatases, PTPN22 promotes M(IL-4+IL-13) activation and reciprocally suppresses M(IFN␥+LPS) [78]. PTPN22 deficient macrophages treated with IL-4 and IL-13 have lower STAT6 phosphorylation and activation hence lower mRNA expression for arginase 1, Mrc1, and FIZZ1, and higher IL-10 production compared to M(IL-4+IL-13) from wild type mice [78].…”

“…PTPN22 deficient macrophages treated with IL-4 and IL-13 have lower STAT6 phosphorylation and activation hence lower mRNA expression for arginase 1, Mrc1, and FIZZ1, and higher IL-10 production compared to M(IL-4+IL-13) from wild type mice [78]. PTPN22 deficient macrophages treated with IFN␥ and LPS have higher NFB activation and higher production of IL-12p70, IL-23, and nitric oxide compared to M(IFN␥+LPS) from wild type mice [78]. Consistent with this, PTPN22 knockdown increases IFN␥-induced pro-inflammatory cytokine production in THP-1 cells, a human myelomonocytic cell line [82].…”

“…It is expressed primarily in hematopoietic cells and can be found in the cytoplasm and nucleus [78]. It contains a C-terminal protein tyrosine phosphatase domain and four prolinerich domains.…”

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

“…We have previously shown that PTPN22 is reduced in the intestine of IBD patients and that it plays a protective role during intestinal inflammation [24]. Further, PTPN22-deficient mice are more affected by DSS-induced colitis [25-27]. One possible explanation for reduced PTPN22 expression might be the fact that TNF-α and IL-1β suppress PTPN22 expression [28].…”