Interleukin-35 as a Key Immunoregulatory Mediator in Steroid-Hyporesponsive Severe Asthma

Jehan Al-Matouq¹Baraa Khalid Salah Al-Sheakly²Narjes Saheb Sharif-Askari³Rabih Halwani³Fatemeh Saheb Sharif-Askari^1*

• ¹University of Sharjah College of Pharmacy, Sharjah, United Arab Emirates
• ²University of Sharjah, Sharjah, United Arab Emirates
• ³University of Sharjah College of Medicine, Sharjah, United Arab Emirates

Severe asthma remains a major unmet clinical challenge, largely due to corticosteroid hyporesponsiveness in a subset of patients. Despite high-dose inhaled or systemic corticosteroids and targeted biologics, chronic airway inflammation often persists, particularly in T helper 2 (Th2)-low, neutrophilic, and mixed inflammatory phenotypes. Corticosteroid failure in severe asthma reflects not only excessive inflammation but a fundamental breakdown of immune regulatory mechanisms. At the molecular level, steroid hyporesponsiveness is associated with impaired glucocorticoid receptor (GR) signaling, including an altered GRα/GRβ balance, sustained activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, oxidative stress–mediated histone deacetylase 2 (HDAC2) dysfunction, and epigenetic stabilization of pro-inflammatory transcription. Concurrently, regulatory immune networks—particularly regulatory T and B cells that normally enforce immune tolerance and promote inflammatory resolution—are quantitatively and functionally compromised. Although biologics targeting immunoglobulin E (IgE), interleukin-5 (IL-5)/IL-5 receptor alpha (IL-5Rα), and IL-4 receptor alpha (IL-4Rα) have improved type-2-high asthma, their efficacy in steroid-hyporesponsive disease remains limited, as they do not restore immune regulation or glucocorticoid sensitivity. In this context, IL-35 has emerged as a uniquely positioned immunoregulatory cytokine. Produced mainly by regulatory T and B cells, IL-35 suppresses Th17-driven and innate immune inflammation, inhibits MAPK and NF-κB signaling, expands regulatory immune networks through infectious tolerance, and stabilizes epithelial barrier integrity. Importantly, IL-35 restores corticosteroid sensitivity in experimental models by targeting key drivers of steroid resistance. This review highlights IL-35 as a potential therapeutic target for managing steroid-hyporesponsive severe asthma by linking asthma endotypes, steroid resistance mechanisms, and IL-35 biology.