Myeloid-Intrinsic Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2) Programs Hematopoietic Stem Cells Towards Pro-Inflammatory Macrophages 2309892

Abstract Introduction Protein tyrosine phosphatase non-receptor type 2 (PTPN2) suppresses inflammatory signaling, and its loss is linked to several inflammatory diseases. PTPN2 helps dampen mucosal inflammation by shifting macrophage balance from pro-inflammatory M1 to protective M2 types. While PTPN2’s role in macrophage activation is known, its impact on myeloid progenitor cells and macrophage differentiation remains unclear, potentially offering new stem cell therapy opportunities. Methods We studied myelopoiesis and macrophage responses in myeloid-specific PTPN2-deficient mice (KO) and wild-type controls (WT), both under naïve conditions and after M2 macrophage polarization via helminth infection. A congenic bone marrow chimera strategy was used to assess cell-intrinsic effects of PTPN2 on monocyte-to-macrophage transition and survival, and Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) was performed on the WT and KO donor cells. Results Flow cytometry showed that PTPN2 KO mice had increased Ly6C-Hi P1 inflammatory monocytes and decreased P4 resident macrophages in the colon, with heightened M1 activation post-infection. This led to improved helminth clearance but increased lung and intestinal inflammation. KO donor cells had a reconstitution advantage over WT cells, coupled with a differentiation blockade and accumulation of P1 monocytes. After infection, KO donor cells maintained elevated inflammatory monocytes in the colon, stabilizing local inflammation. CITE-seq revealed increased transcriptional activity and enrichment of antigen presentation and cell survival genes in PTPN2-deficient cells. Conclusion Overall, myeloid-intrinsic PTPN2 deficiency primes the myeloid compartment for inflammation, boosting immunity to helminth infection but sustaining mucosal inflammation. PTPN2 regulates macrophage activation during myelopoiesis, restraining excessive monocyte-to-macrophage transition and limiting cell survival and antigen presentation. Funding Source The National Institutes of Health (RO1AI135195 to DM and MGN) and the UCR Division of Biomedical Sciences (Burden/Pease Fellowship to SA) Topic Categories Mucosal and Regional Immunology (MUC)