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.
Highlights
We demonstrated that Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in dendritic cell (DC) affects immune cell infiltrations in the lamina propria, but its presence in DCs seems to be dispensable in the context of colonic inflammation
Together with the observation that the loss of PTPN2 in DCs affects immune cell populations, this led us to expect that PTPN2 in DCs would exert a key role in regulating immune responses during intestinal inflammation
In a model of acute colitis, the extent of colitis in PTPN2fl/fl xCD11cCre was comparable to their wild-type littermates, whereas in a model of chronic colitis, mice with PTPN2-deficient DCs tended to exhibit even less severe intestinal inflammation, while there was no effect in T cell-mediated colitis
Summary
Current hypotheses suggest that genetic and environmental factors contribute to the pathology of inflammatory bowel disease (IBD) by driving uncontrolled and excessive immune responses against the commensal intestinal microbiota [1]. Genome-wide association studies identified variants in the gene locus encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2; known as T cell protein tyrosine phosphatase (TCPTP)) to be associated with IBD, as well as with other chronic inflammatory diseases, including type. First insights into the mechanisms by which PTPN2 variants might promote susceptibility to inflammatory disorders came from the observation that PTPN2 negatively regulates proinflammatory signaling cascades and that presence of the disease-associated variants results in a loss of function PTPN2 protein [5,6,7,8]. Well-described PTPN2 targets include signaling transducer and activator of transcription (STAT) molecules, mitogen-activated protein kinase (MAPK) P38, c-Jun
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