Hepatocyte SHP-1 is a Critical Modulator of Inflammation During Endotoxemia
Abstract 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 in...
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| Autores principales: | , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/f0f64b4bc663496380bc031511babb6f |
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| Sumario: | Abstract 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. |
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