IL-35 interferes with splenic T cells in a clinical and experimental model of acute respiratory distress syndrome

• Published in: International immunopharmacology 2019-02, Vol.67, p.386-395
• Main Authors: Wang, Chuan-jiang, Zhang, Mu, Wu, Hua, Lin, Shi-hui, Xu, Fang
• Format: Article
• Language: English
• Subjects: Acute respiratory distress syndrome; Aged; Alveoli; Animal models; Animals; Antibodies; Antibodies, Neutralizing - therapeutic use; Biomarkers - blood; Bronchoalveolar Lavage Fluid; Bronchus; Case-Control Studies; CD25 antigen; CD4 antigen; Cecum; Chemokines; Cytokines; Female; Foxp3 protein; Gene Expression Regulation - drug effects; Humans; IL-35; Immunology; Inflammation; Interleukin 12; Interleukin 23; Interleukin 27; Interleukin 6; Interleukins - blood; Interleukins - metabolism; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lung; Lungs; Lymphocytes; Lymphocytes T; Male; Mathematical models; Mice; Middle Aged; Neutralizing; Patients; Regulatory T cells; Respiratory distress syndrome; Respiratory Distress Syndrome - immunology; Respiratory therapy; Spleen; T-Lymphocytes - classification; T-Lymphocytes - physiology; Therapeutic applications; Tumor necrosis factor-α; Uncontrolled inflammation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2018.12.024

Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome with uncontrolled inflammation that is a central issue. Its main characteristic is inflammatory mediators and cytokines as well as agglutinating chemokines that injure target cells. Interleukin (IL)-35 is a newly identified IL-12 cytokine family member with structural similarities to other IL-12, IL-23, and IL-27 cytokines but unique immunological functions. How IL-35 functions in ARDS is unclear. The purpose of our study was to determine what role IL-35 played in the development of ARDS. Here we found serum IL-35 concentrations were significantly elevated in patients with ARDS relative to healthy people. Moreover, we established a mouse model of lipopolysaccharide- and cecal ligation and puncture-induced ARDS treated with neutralizing antibodies (anti-IL-35 Ebi3 or anti-IL-35 P35); the results showed that lung injury occurred more often than in untreated models and the inflammatory cytokines CXCL-1, tumor necrosis factor alpha, IL-6, and IL-17A increased significantly after neutralizing antibody treatment in bronchoalveolar lavage fluid and serum. Therefore IL-35 can protect against the development of ARDS. Even more interesting in our study was that we discovered IL-35 expression differed between lung and spleen across different ARDS models, which further demonstrated that the spleen likely has an important role in extrapulmonary ARDS model only, improving the ratio of CD4+/CD4+CD25+Foxp3+(Tregs). Meanwhile in our clinical work, we also found that the concentration of IL-35 and the ratio of CD4+/Treg in the serum are higher and the mortality is lower than those with the spleen deficiency in patients with extrapulmonary ARDS. Therefore, IL-35 is protective in ARDS by promoting the ratio of splenic CD4+/Tregs in extrapulmonary ARDS, and as such, may be a therapeutic target. •IL-35was protective against the development of ARDS.•In the CLP and LPS-induced ARDS model (splenectomized and non splenectomized groups), we found that spleen was not involved in IL-35 secretion in pulmonary ARDS but had a role in extrapulmonary ARDS.•IL-35 could promote the ratio of splenic CD4+/CD4+CD25+Foxp3+(Tregs) in extrapulmonary ARDS only, but not in pulmonary ARDS.