IL-17RA/IL-17RC Blockade Restores Fibrinolytic Balance in Bleomycin-induced Acute Lung Injury.

INTRODUCTION

Interleukin-17A (IL-17A) signalling disrupts fibrinolysis and drives inflammation and fibrotic remodelling in acute lung injury (ALI). IL-17A signals through a heterodimeric complex of IL-17RA and IL-17RC, initiating a cascade of immunological responses, including the synthesis of chemokines and inflammatory mediators. This leads to compromised epithelial integrity and barrier dysfunction. To determine the therapeutic potential of IL-17RA and IL-17RC neutralising antibodies on inflammation and the fibrinolytic system in a bleomycin (BLM)-induced ALI model.

METHODS

A549 cells and C57BL/6 mice were used to study the effects of neutralising IL-17RA and IL-17RC. ALI was induced in both models using BLM. A549 cells were subsequently treated with IL-17RA and IL-17RC neutralising antibodies. In mice, ALI was induced via intranasal administration of BLM. Neutralising antibodies against IL-17RA and IL-17RC were administered intranasally. Collected lung tissues and cell pellets were assessed for expression of the fibrinolytic system and inflammation.

RESULTS

Our study demonstrates the active involvement of IL-17 receptors, IL-17RA, and IL17RC in ALI. BLM treatment significantly increased PAI-1 expression ~ 3.5-fold, whereas neutralisation of IL-17RA or IL-17RC markedly reduced PAI-1 levels by over 90% compared to the BLM treated group, while restoring the expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) and suppressing pro-inflammatory cytokines TNF-α and IL-6.

DISCUSSION: This study reveals that neutralisation of IL-17RA or IL-17RC in BLM-induced ALI reduced inflammation and restored normal fibrinolytic balance.

CONCLUSION

Our study suggests that IL-17RA and IL-17RC play a major role in inflammation and the regulation of fibrinolysis during ALI. Targeting these receptors can mitigate lung injury and restore normal fibrinolytic activity, highlighting a novel receptor-specific IL-17 blockade as a potential therapeutic strategy to limit lung injury and improve ALI and Acute respiratory distress syndrome (ARDS) outcomes.