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

Asthma is a heterogeneous disorder, evidenced by distinct types of inflammation resulting in different responsiveness to therapy with glucocorticoids (GCs). Tumor necrosis factor alpha (TNF alpha) is involved in asthma pathogenesis, but anti-TNF alpha therapies have not proven broadly effective. The effects of anti-TNF alpha treatment on steroid resistance have never been assessed. We investigated the role of TNF alpha 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 TNF alpha blockade restores the therapeutic effects of GCs in the GC-insensitive model. An adoptive transfer indicated that the TNF alpha-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 TNF alpha 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 TNFa reduces the responsiveness to GCs in a mouse model of neutrophilic airway inflammation. Thus antagonizing TNFa may offer a new strategy for therapeutic intervention in GC-resistant asthma.