Correlation Between Early Plasma Interleukin 37 Responses With Low Inflammatory Cytokine Levels and Benign Clinical Outcomes in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract

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.

Current Understanding of IL-37 in Human Health and Disease

“…SARS-CoV-2 infection is characterized by an increased level of IL-37 in the plasma (108). Higher early IL-37 response is associated with an earlier viral RNA negative status, chest CT image improvement, and cough relief compared to the patients with lower IL-37 level in the plasma (108). Moreover, higher IL-37 is associated with lower IL-6 and IL-8 and higher IFN-a, and promotes biochemical homeostasis compared to the low-IL-37 group, while low IL-37 combined with high CRP and IL-8 levels predicts a poor clinical prognosis (108).…”

“…Higher early IL-37 response is associated with an earlier viral RNA negative status, chest CT image improvement, and cough relief compared to the patients with lower IL-37 level in the plasma (108). Moreover, higher IL-37 is associated with lower IL-6 and IL-8 and higher IFN-a, and promotes biochemical homeostasis compared to the low-IL-37 group, while low IL-37 combined with high CRP and IL-8 levels predicts a poor clinical prognosis (108). IL-37 administration attenuates lung inflammation and damage of the respiratory tissue while maintaining type I IFN, consequently keeping safe the function of vital organs (108).…”

“…Moreover, higher IL-37 is associated with lower IL-6 and IL-8 and higher IFN-a, and promotes biochemical homeostasis compared to the low-IL-37 group, while low IL-37 combined with high CRP and IL-8 levels predicts a poor clinical prognosis (108). IL-37 administration attenuates lung inflammation and damage of the respiratory tissue while maintaining type I IFN, consequently keeping safe the function of vital organs (108). Thus, IL-37, by blocking IL-1 (109,110), may be a potential therapeutic agent to combat SARS-CoV-2 infection, and IL-37, IL-8, and CRP may be used as biomarkers to recognize severe clinical cases.…”

Interleukin-37 is down-regulated in serum of patients with severe coronavirus disease 2019 (COVID-19)

“…In this context, the cytokine storm phenomenon has been presented as a potential cause of acute respiratory distress syndrome and multiple organ failure in cases with severe COVID-19, although the evidence is not conclusive [8] . IL-37 is one such cytokine that has been proposed to have a role in immunopathogenesis of COVID-19 but the data in this regard are not overwhelming [9] , [10] .…”

Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19

“…However, it is unclear whether the increased IL-37 results from or results in such clinical manifestations. The possible mechanism of the anti-inflammatory role of IL-37 may be by antagonising inflammatory responses while retaining type I interferon, subsequently maintaining the functionalities of vital organs (90). The role of IL-37 in COVID-19 is supported by the findings in influenza viral infection, showing that IL-37 ameliorates influenza pneumonia in vivo (91).…”