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

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 xLyz2 (Tnfaip3 ) mice were crossed to Il17ra mice, generating Tnfaip3 Il17ra mice and subjected to an HDM-driven airway inflammation model.

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