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

Abstract

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: Tnfaip3^fl/fl xLyz2^+/cre (Tnfaip3^LysM-KO ) mice were crossed to Il17ra^KO mice, generating Tnfaip3^LysM Il17ra^KO mice and subjected to an HDM-driven airway inflammation model.

Results: Both eosinophilic and neutrophilic inflammation observed in HDM-exposed WT and Tnfaip3^LysM-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, Tnfaip3^LysM-KO and Il17ra^KO mice, whereas mucus-producing cells in Tnfaip3^LysM-KO Il17ra^KO mice were reduced compared to controls. Strikingly, spontaneous accumulation of pulmonary Th1, Th17 and γδ-17 T cells was observed in Tnfaip3^LysM-KO Il17ra^KO 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 Tnfaip3^LysM-KO Il17ra^KO 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 Tnfaip3^LysM-KO and Tnfaip3^LysM-KO Il17ra^KO 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.

Keywords: IL-17A; asthma; neutrophils.