Necrostatin-1 enhances the resolution of inflammation by specifically inducing neutrophil apoptosis.

Abstract

Neutrophils play a central role in innate immunity and are rapidly recruited to sites of infection and injury. Neutrophil apoptosis is essential for the successful resolution of inflammation. Necrostatin-1 (Nec-1,methyl-thiohydantoin-tryptophan (MTH-Trp)), is a potent and specific inhibitor of necroptosis[1] (a newly identified type of cell death representing a form of programmed necrosis or regulated non apoptotic cell death) by inhibiting the receptor interacting protein 1(RIP1) kinase. Here we report that Nec-1 specifically induces caspase-dependent neutrophils apoptosis and overrides powerful anti-apoptosis signaling from survival factors such as GM-CSF and LPS. We showed that Nec-1 markedly enhanced the resolution of established neutrophil-dependent inflammation in LPS-induced acute lung injury in mice. We also provided evidence that Nec-1 promoted apoptosis by reducing the expression of the anti-apoptotic protein Mcl-1 and increasing the expression of pro-apoptotic protein Bax. Thus, Nec-1 is not only an inhibitor of necroptosis, but also a promoter of apoptosis, of neutrophils, enhancing the resolution of established inflammation by inducing apoptosis of inflammatory cells. Our results suggest that Nec-1 may have potential roles for the treatment of diseases with increased or persistent inflammatory responses.

• Authors: Hongyu Jie, Yi He, Xuechan Huang, Qingyou Zhou, Yanping Han, Xing Li, Yongkun Bai, Erwei Sun
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 15 Pg. 19367-81 (Apr 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27027357 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Imidazoles
• Indoles
• Inflammation Mediators
• necrostatin-1
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Acute Lung Injury (drug therapy, metabolism)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Cells, Cultured
• Cytokines (metabolism)
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Inflammation (metabolism, prevention & control)
• Inflammation Mediators (metabolism)
• Lung (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Neutrophils (drug effects, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)