Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus

Author:

Han Xinai12,Zhang Xiaoming23,Song Rui12,Li Shiqi23,Zou Shujing23,Tan Quanguang23,Liu Tianyang23,Luo Shugeng23,Wu Zhe23,Jie Hongyu12ORCID,Wang Jinhong23ORCID

Affiliation:

1. Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630 Guangdong, China

2. Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630 Guangdong, China

3. Department of Respiration, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China

Abstract

Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.

Funder

Guangzhou Science and Technology Program key projects

Publisher

Hindawi Limited

Subject

Immunology,General Medicine,Immunology and Allergy

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