House dust mite‐driven neutrophilic airway inflammation in mice with TNFAIP3‐deficient myeloid cells is IL‐17‐independent

Summary Background Asthma is a heterogeneous disease of the airways that involves several types of granulocytic inflammation. Recently, we have shown that the activation status of myeloid cells regulated by TNFAIP3/A20 is a crucial determinant of eosinophilic or neutrophilic airway inflammation. However, whether neutrophilic inflammation observed in this model is dependent on IL‐17 remains unknown. Objective In this study, we investigated whether IL‐17RA‐signalling is essential for eosinophilic or neutrophilic inflammation in house dust mite (HDM)‐driven airway inflammation. Methods Tnfaip3fl/flxLyz2+/cre (Tnfaip3LysM‐KO) mice were crossed to Il17raKO mice, generating Tnfaip3LysMIl17raKO mice and subjected to an HDM‐driven airway inflammation model. Results Both eosinophilic and neutrophilic inflammation observed in HDM‐exposed WT and Tnfaip3LysM‐KO mice respectively were unaltered in the absence of IL‐17RA. Production of IL‐5, IL‐13 and IFN‐γ by CD4+ T cells was similar between WT, Tnfaip3LysM‐KO and Il17raKO mice, whereas mucus‐producing cells in Tnfaip3LysM‐KOIl17raKO mice were reduced compared to controls. Strikingly, spontaneous accumulation of pulmonary Th1, Th17 and γδ‐17 T cells was observed in Tnfaip3LysM‐KOIl17raKO mice, but not in the other genotypes. Th17 cell‐associated cytokines such as GM‐CSF and IL‐22 were increased in the lungs of HDM‐exposed Tnfaip3LysM‐KOIl17raKO mice, compared to IL‐17RA‐sufficient controls. Moreover, neutrophilic chemo‐attractants CXCL1, CXCL2, CXCL12 and Th17‐promoting cytokines IL‐1β and IL‐6 were unaltered between Tnfaip3LysM‐KO and Tnfaip3LysM‐KOIl17raKO mice. Conclusion and Clinical Relevance These findings show that neutrophilic airway inflammation induced by activated TNFAIP3/A20‐deficient myeloid cells can develop in the absence of IL‐17RA‐signalling. Neutrophilic inflammation is likely maintained by similar quantities of pro‐inflammatory cytokines IL‐1β and IL‐6 that can, independently of IL‐17‐signalling, induce the expression of neutrophil chemo‐attractants.