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

• Published in: Scientific reports 2017-05, Vol.7 (1), p.2218-10, Article 2218
• Main Authors: Adhikari, Anupam, Martel, Caroline, Marette, André, Olivier, Martin
• Format: Article
• Language: English
• Subjects: 13; 13/106; 631/250/256/1980; 631/326/421; Animals; Biomarkers; Cytokines; Disease Models, Animal; Disease Progression; Disseminated infection; Endotoxemia; Endotoxemia - etiology; Endotoxemia - metabolism; Endotoxemia - pathology; Hepatocytes; Hepatocytes - metabolism; Humanities and Social Sciences; Inflammation; Inflammation Mediators - metabolism; Inoculation; Lipopolysaccharides; Lipopolysaccharides - adverse effects; Liver; Mice; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Neutrophils - immunology; Neutrophils - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Rodents; Science; Science (multidisciplinary); SHP-1 protein; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-α; Tyrosine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02512-7

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.