Macrophages Compensate for Loss of Protein Tyrosine Phosphatase N2 in Dendritic Cells to Protect from Elevated Colitis.

Abstract

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Mice lacking PTPN2 in dendritic cells (DCs) develop skin and liver inflammation by the age of 22 weeks due to a generalized loss of tolerance leading to uncontrolled immune responses. The effect of DC-specific PTPN2 loss on intestinal health, however, is unknown. The aim of this study was to investigate the DC-specific role of PTPN2 in the intestine during colitis development. PTPN2fl/flxCD11cCre mice were subjected to acute and chronic DSS colitis as well as T cell transfer colitis. Lamina propria immune cell populations were analyzed using flow cytometry. DC-specific PTPN2 deletion promoted infiltration of B and T lymphocytes, macrophages, and DCs into the lamina propria of unchallenged mice and elevated Th1 abundance during acute DSS colitis, suggesting an important role for PTPN2 in DCs in maintaining intestinal immune cell homeostasis. Surprisingly, those immune cell alterations did not translate into increased colitis susceptibility in acute and chronic DSS-induced colitis or T cell transfer colitis models. However, macrophage depletion by clodronate caused enhanced colitis severity in mice with a DC-specific loss of PTPN2. Loss of PTPN2 in DCs affects the composition of lamina propria lymphocytes, resulting in increased infiltration of innate and adaptive immune cells. However, this did not result in an elevated colitis phenotype, likely because increased infiltration of macrophages in the intestine upon loss of PTPN2 loss in DCs can compensate for the inflammatory effect of PTPN2-deficient DCs.

• Authors: Larissa Hering, Egle Katkeviciute, Marlene Schwarzfischer, Anna Niechcial, Julianne B Riggs, Marcin Wawrzyniak, Kirstin Atrott, Marnix van de Sande, Silvia Lang, Burkhard Becher, Gerhard Rogler, Michael Scharl, Marianne R Spalinger
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 13 (Jun 25 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34201918 (Publication Type: Journal Article)

Chemical References

• STAT1 Transcription Factor
• Stat1 protein, mouse
• Dextran Sulfate
• Protein Tyrosine Phosphatase, Non-Receptor Type 2
• Ptpn2 protein, mouse

Topics

• Animals
• Colitis (etiology, metabolism, pathology)
• Dendritic Cells (immunology, metabolism)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Disease Susceptibility
• Intestinal Mucosa (immunology, metabolism, pathology)
• Macrophages (immunology, metabolism)
• Mice
• Mice, Transgenic
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 (deficiency, genetics, metabolism)
• STAT1 Transcription Factor (metabolism)
• Severity of Illness Index
• Signal Transduction
• T-Lymphocyte Subsets (immunology, metabolism, pathology)