Interleukin-6 is significantly increased in severe pneumonia after allo-HSCT and might induce lung injury via IL-6/sIL-6R/JAK1/STAT3 pathway

Abstract Background Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokines, including interleukin 6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe coronavirus disease 2019 (COVID-19), we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia after allo-HSCT and explore its underlying mechanism. Methods Serum cytokine levels were prospectively measured in patients with severe and nonsevere pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiments using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI. Results Serum IL-6 and soluble IL-6 receptor (sIL-6R) levels were higher in the severe pneumonia group than in the nonsevere group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses. Conclusions IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.