Research Papers: Autophagy and Cell Death:

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

Hongyu Jie, Yi He, Xuechan Huang, Qingyou Zhou, Yanping Han, Xing Li, Yongkun Bai and Erwei Sun _

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Oncotarget. 2016; 7:19367-19381. https://doi.org/10.18632/oncotarget.8346

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Hongyu Jie1,2, Yi He1,2, Xuechan Huang1,2, Qingyou Zhou1,2, Yanping Han1,2,3, Xing Li1,2, Yongkun Bai1,2 and Erwei Sun1,2

1 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China

2 Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China

3 Hospital of South China Normal University, Guangzhou, Guangdong , China

Correspondence to:

Erwei Sun , email:

Keywords: neutrophil, apoptosis, inflammation, Necrostatin-1

Received: August 04, 2015 Accepted: March 08, 2016 Published: March 24, 2016


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.

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