Association of Neutrophil Extracellular Traps with Fistula Healing in Patients with Complex Perianal Fistulizing Crohn’s Disease

Author:

Cao Dongxing1,Qian Keyu2,Zhao Ying3,Hong Jie3,Chen Haoyan3,Wang Xiaohui4,Yang Nailin1,Zhang Cheng1,Cao Jingkai4,Jia Keyu2,Wu Guangyu5,Zhu Mingming6,Shen Jun7,Zhang Ye2,Cui Zhe18ORCID,Wang Zheng1

Affiliation:

1. Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China

2. Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200444 , China

3. State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive Disease; Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200001 , China

4. Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200444 , China

5. Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200444 , China

6. Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China

7. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University , Shanghai , China

8. Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , No.1058, Huan Zhen Bei Rd, Baoshan District, Shanghai 200444 , China

Abstract

Abstract Background and Aims Perianal fistulizing Crohn’s disease [pfCD] is a disabling phenotype of Crohn’s disease [CD] with suboptimal outcomes. We assessed neutrophil extracellular traps [NETs] in perianal fistulas and implicated their roles in pfCD healing. Methods Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NET components, including myeloperoxidase [MPO], neutrophil elastase [NE] and citrullinated histone H3 [CitH3], were identified using immunofluorescence. Serum infliximab [IFX], anti-IFX antibodies, and tissue levels of IFX, adalimumab [ADA], MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV [PAD4], tumour necrosis factor [TNF]-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with quantitative PCR. Results Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-sequencing revealed differences in neutrophil associated pathways between unhealed and healed fistulas. NET components [MPO/NE/CitH3] were detectable in the fistulas and were parallel with the levels of PAD4. Eleven of 21 [52%] patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. Conclusions NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.

Funder

National Natural Science Foundation of China

Shanghai Science and Technology Innovation Initiative

Shanghai Baoshan District Science and Technology Foundation

Ren Ji Hospital Cultivated Funding for Clinical Research Innovation

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,General Medicine

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