Hepatocyte SHP-1 is a Critical Modulator of Inflammation During Endotoxemia

Liver hepatocytes (Hep) are known to be central players during the inflammatory response to systemic infection. Interestingly, the protein tyrosine phosphatases (PTP) SHP-1, has been recognized as a major regulator of inflammation; however their implication in the control of Hep-mediated inflammatory response is still unknown. To study its implication in the regulation of the Hep-mediated inflammatory response during endotoxemia, Cre-Lox mice with a Hep-specific Ptpn6 deletion (Ptpn6 (H-KO)) were injected with LPS. In contrast to the wild-type mice (Ptpn6 (f/f)) that started to die by 24 hrs post-inoculation, the Ptpn6 (H-KO) mice exhibited mortality by 6 hrs. In parallel, higher amounts of metabolic markers, pro-inflammatory mediators and circulating cytokines were detected in Ptpn6 (H-KO) mice. Primary Hep obtained from Ptpn6 (H-KO), also showed increased secretion of pro-inflammatory cytokines and nitric oxide (NO) comparatively to its wild type (Ptpn6 (f/f)) counterpart. Pharmacological approaches to block TNF-α and NO production protected both the Ptpn6 (f/f) and the Ptpn6 (H-KO) mice against deadly LPS-mediated endotoxemia. Collectively, these results establish hepatocyte SHP-1 is a critical player regulating systemic inflammation. Our findings further suggest that SHP-1 activation could represent a new therapeutic avenue to better control inflammatory-related pathologies.