Interleukin 6 Is Significantly Increased in Severe Pneumonia After Allo-Hematopoietic Stem Cell Transplantation and Might Induce Lung Injury via IL-6/sIL-6R/JAK1/STAT3 Pathway

By
Jing-Rui Zhou
Yi Liao
Le-Qing Cao
Rui Ma
Yun He
Na Li
Dan-Ping Zhu
Xiao-Su Zhao
Xiao-Jun Huang
Yu-Qian Sun
January 20, 2025
0 min

The Journal Of Infectious Diseases

Overview

This study identifies elevated serum IL-6 and soluble IL-6 receptor levels in patients with severe pneumonia following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It demonstrates that IL-6 trans-signaling via the IL-6/sIL-6R/JAK1/STAT3 pathway contributes to pulmonary microvascular endothelial cell injury and acute lung injury, suggesting a potential therapeutic target.

Background

Allogeneic hematopoietic stem cell transplantation is a curative treatment for hematologic diseases but is frequently complicated by pneumonia, which can progress to severe forms with high mortality. The pathogenesis of severe pneumonia post-allo-HSCT remains poorly understood, with limited effective antimicrobial treatments. Pulmonary microvascular endothelial cell dysfunction and systemic hyperinflammation, including elevated cytokines like interleukin 6 (IL-6), are implicated in acute lung injury and respiratory distress syndromes. Understanding IL-6's role may reveal new therapeutic avenues.

Data Highlights

Parameter	Severe Pneumonia Group	Nonsevere Pneumonia Group	Control Group
Serum IL-6 Levels	Elevated	Lower	Baseline
Serum sIL-6R Levels	Elevated	Lower	Baseline
Incidence of Severe Pneumonia	25%-43%	N/A	N/A
Mortality Rate	High	Lower	N/A

Key Findings

Serum IL-6 and soluble IL-6 receptor levels were significantly higher in patients with severe pneumonia compared to those with nonsevere pneumonia post-allo-HSCT.
Elevated IL-6 levels correlated with disease progression and severity in pneumonia after allo-HSCT.
In a mouse model of acute lung injury, preventive IL-6 blockade reduced lung injury and improved survival outcomes.
IL-6 trans-signaling via the IL-6/sIL-6R complex caused more severe damage to pulmonary microvascular endothelial cells than classical IL-6 signaling.
Blocking the JAK1/STAT3 pathway with soluble glycoprotein 130 and ruxolitinib effectively reduced inflammatory responses induced by IL-6 trans-signaling in endothelial cells.

Clinical Implications

Monitoring IL-6 and sIL-6R levels in patients post-allo-HSCT may help identify those at risk for severe pneumonia and guide early intervention. Therapeutic strategies targeting the IL-6 trans-signaling pathway, such as IL-6 blockade or JAK1/STAT3 inhibition, hold promise for reducing lung injury and improving survival in this vulnerable population. These findings support further clinical evaluation of IL-6 pathway inhibitors in severe pneumonia following allo-HSCT.

Conclusion

Elevated IL-6 and its trans-signaling pathway play a pivotal role in the pathogenesis of severe pneumonia and acute lung injury after allo-HSCT. Targeting this pathway represents a promising therapeutic approach to mitigate lung damage and improve outcomes in affected patients.

References

Peking University People's Hospital Study 2019-2022 -- Elevated Levels of Interleukin 6 in Severe Pneumonia Following Allo-Hematopoietic Stem Cell Transplantation