Early plasma IL-37 responses accompanied with low inflammatory cytokines correlate with benign clinical outcomes during SARS-CoV-2 infection

Li, Ang; Ling, Yun; Song, Zhigang; Cheng, Xiaobo; Ding, Longfei; Jiang, Rendi; Fu, Weihui; Liu, Yan; Hu, Huiliang; Yuan, Songhua; Chen, Jian; Zhu, Cuisong; Fan, Jun; Wang, Jing; Jin, Yanling; Zhang, Miaomiao; Zhu, Lingyan; Sun, Peng; Zhang, Linxia; Qin, Ran; Zhang, Wei; Qiu, Chenli; Shen, Yinzhong; Zhang, Lin; Shi, Zhengli; Zhao, Chen; Zhu, Tongyu; Lu, Hongzhou; Zhang, Xiaoyan; Xu, Jianqing

BACKGROUND: The immune protective mechanisms during SARS-CoV-2 infection remain to be deciphered for the development of an effective intervention approach. METHODS: We examined early responses of IL-37, a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients prior to any clinical intervention and determined its correlation with clinical prognosis. RESULTS: Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses correlated with earlier viral RNA negative conversion, chest CT image improvement and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower IL-6 and IL-8 and higher IFN-α and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and CRP. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2 (hACE2)-transgenic mice infected with SARS-CoV-2. CONCLUSIONS: Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I IFN, thereby maintaining the functionalities of vital organs. IL-37, IL-8 and CRP might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.