Neutralizing TNFα restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation

Abstract

Asthma is a heterogeneous disorder, evidenced by distinct types of inflammation resulting in different responsiveness to therapy with glucocorticoids (GCs). Tumor necrosis factor α (TNFα) is involved in asthma pathogenesis, but anti-TNFα therapies have not proven broadly effective. The effects of anti-TNFα treatment on steroid resistance have never been assessed. We investigated the role of TNFα blockade using etanercept in the responsiveness to GCs in two ovalbumin-based mouse models of airway hyperinflammation. The first model is GC sensitive and T helper type 2 (Th2)/eosinophil driven, whereas the second reflects GC-insensitive, Th1/neutrophil-predominant asthma subphenotypes. We found that TNFα blockade restores the therapeutic effects of GCs in the GC-insensitive model. An adoptive transfer indicated that the TNFα-induced GC insensitivity occurs in the non-myeloid compartment. Early during airway hyperinflammation, mice are GC insensitive specifically at the level of thymic stromal lymphopoietin (Tslp) transcriptional repression, and this insensitivity is reverted when TNFα is neutralized. Interestingly, TSLP knockout mice displayed increased inflammation in the GC-insensitive model, suggesting a limited therapeutic application of TSLP-neutralizing antibodies in subsets of patients suffering from Th2-mediated asthma. In conclusion, we demonstrate that TNFα reduces the responsiveness to GCs in a mouse model of neutrophilic airway inflammation. Thus antagonizing TNFα may offer a new strategy for therapeutic intervention in GC-resistant asthma.

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

“…A key role for the inflammatory cytokine TNFα was also recently demonstrated in a model of steroid-resistant neutrophilic airway inflammation induced by sensitization with complete Freund's adjuvant (CFA), where inhibition of TNFα could restore steroid sensitivity. 40 These findings provide support for key roles of innate immune inflammation in the development of steroid resistance.…”

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

“…81 In an experimental model of Th1/neutrophil-predominant asthma, TNFa reduced the responsiveness to steroids and neutralization of TNFa using etanercept restored glucocorticoid sensitivity. 82 Recently, the TNF superfamily member, LIGHT, has been implicated as a mediator in asthmatic airway inflammation. Human bronchial epithelial cells express the receptor for LIGHT, the lymphotoxin b receptor (LTbR) and upon stimulation with LIGHT release IL-6, oncostatin M, MCP-1, growth-regulated protein a and IL-8.…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…In contrast, mice sensitized with aluminum hydroxide (Alum) display a conventional Th2/eosinophil-driven inflammation that responds well to GCs [126]. Recently, we found that neutralization of TNF, using etanercept, restores GC sensitivity in the GC-resistant OVA-CFA model [127]. Furthermore, cytokine inhibition was found to restore GC sensitivity also in GCR patients, as the IL-1 receptor antagonist anakinra was found to be revert GC sensitivity in patients with corticosteroid-resistant autoimmune inner ear disease [128].…”