Human-relevant Ptpn6 mutation alters immune and hepatic functions during aging

Src homology region 2-containing phosphatase 1 (SHP-1), encoded by the protein tyrosine phosphatase non-receptor type 6 (PTPN6), regulates immune and metabolic signaling pathways. Although its functions in immune cells and insulin-responsive tissues are separately established, its integrative function in immunometabolic regulation remains unclear. A damaging variant in the PTPN6 gene (Ala455Thr) was discovered in a French-Canadian family and found to be the cause of early-onset emphysema. Using mice carrying this whole-body human-relevant mutation, we studied immunometabolic phenotypes across aging. Old mutant mice showed decreased body, liver and adipose tissue weights, improved glucose tolerance, and enhanced hepatic insulin sensitivity. Despite improved metabolic parameters, aged mutant mice developed liver abnormalities, including increased fibrosis and aberrant immune cell infiltration. Transcriptomic and histological analyses revealed an age-associated accumulation of intrahepatic B lymphocytes and macrophages, accompanied by increased SHP-1 protein levels and activation of Signal transducer and activator of transcription 3 (STAT3) signaling. Experiments in primary hepatocytes and old hepatocyte-specific Ptpn6 knockout mice suggest that these alterations are driven by immune rather than intrinsic hepatocyte mechanisms. These findings identify SHP-1 as a critical modulator of liver immune homeostasis during aging and demonstrate that immune cell infiltration contributes to age-related hepatic remodeling under SHP-1 deficiency.