Fibrinogen and Lipopolysaccharide Promote TLR4-Dependent Glucocorticoid Resistance in Airway Mycosis-Driven Allergic Airway Disease

Authors

• Y Zeng
• X Huang
• G Liang
• K Tang
• K E Mauk
• H Sun
• Y Zhang
• Z Zeng
• L Song
• K Polsky
• Y Wu
• C T Landers
• E Z Otukoya
• L H Bimler
• F Kheradmand
• A U Luong
• Y Guo
• J M Knight
• D B Corry

Language

English

Publication Date

8-1-2026

Journal

Mucosal Immunology

DOI

10.1016/j.mucimm.2026.100354

PMID

42219086

PMCID

PMC13617660

PubMedCentral® Posted Date

9-29-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Glucocorticoid-refractory asthma is a severe disease type linked to both T helper type 2 (T2) high and T2 low, neutrophil-high asthma endotypes, but the mechanisms governing glucocorticoid resistance are largely unknown. We show that glucocorticoid-resistant mouse allergic airway disease is linked to airway mycosis and lung-specific production of fibrinogen cleavage products (cryptokines). Mice challenged with the allergenic fungus Aspergillus niger and low-dose inhaled lipopolysaccharide (LPS) showed exaggerated airway hyperresponsiveness (AHR), developed T2 high and neutrophilic airway inflammation recapitulating severe asthma. AHR was not attenuated by glucocorticoid therapy, but required expression of Toll-like receptor 4 (TLR4). Low-dose intranasal LPS alone induced AHR in a manner previously shown for Aspergillus proteinase-derived cryptokines that required TLR4. We show further that cryptokines significantly enhance fibrinogen production in both the mouse lung and from primary human airway epithelial cells and that cryptokine-induced AHR is glucocorticoid resistant. Thus, glucocorticoid resistance in asthma may in part result from airway-specific production of the TLR4 ligands cryptokines and LPS. These findings suggest novel approaches to the management of glucocorticoid-resistant asthma.

Keywords

Animals, Toll-Like Receptor 4, Lipopolysaccharides, Mice, Glucocorticoids, Humans, Asthma, Fibrinogen, Disease Models, Animal, Drug Resistance, Mice, Knockout, Respiratory Hypersensitivity, Th2 Cells, Allergens, Cells, Cultured, Lung, airway mycosis, LPS, airway hyperresponsiveness, glucocorticoid-resistant asthma, T helper cell responses, Fibrinogen, cryptokine, fungus

Published Open-Access

yes

Recommended Citation

Zeng, Y; Huang, X; Liang, G; et al., "Fibrinogen and Lipopolysaccharide Promote TLR4-Dependent Glucocorticoid Resistance in Airway Mycosis-Driven Allergic Airway Disease" (2026). Faculty, Staff and Students Publications. 8789.
https://digitalcommons.library.tmc.edu/baylor_docs/8789