title: 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.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Jie
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Xuechan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Qingyou
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.|Hospital of South China Normal University, Guangzhou, Guangdong, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.|Institute of Clinical Immunology, Academy of Orthopedics, Guangzhou, Guangdong, China.
authors.forename: Erwei
authors.initials: E
authors.lastname: Sun
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D007093:Imidazoles; D007211:Indoles; D018836:Inflammation Mediators; C507699:necrostatin-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Necrostatin-1; apoptosis; inflammation; neutrophil