IL-17RA in Non-Hematopoietic Cells Controls CXCL-1 and 5 Critical to Recruit Neutrophils to the Lung of Mycobacteria-Infected Mice during the Adaptive Immune Response.

During chronic infection with Mycobacterium tuberculosis (Mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. Neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. Neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. Signals that regulate neutrophil recruitment to the lung during mycobacterial infection need to be better understood. We demonstrated here, in the mouse model, that neutrophils were recruited to the lung in two waves after intranasal infection with virulent Mtb or the live attenuated vaccine strain Bacillus Calmette Guérin (BCG). A first wave of neutrophils was swiftly recruited, followed by a subsequent adaptive wave that reached the lung together with IFN-γ- and IL-17A-producing T cells. Interestingly, the second neutrophil wave did not participate to mycobacteria control in the lung and established contacts with T cells. The adaptive wave was critically dependent on the expression of IL-17RA, the receptor for IL-17A, expressed in non-hematopoietic cells. In absence of this receptor, curtailed CXCL-1 and 5 production in the lung restrained neutrophil recruitment. CXCL-1 and 5 instillation reconstituted lung neutrophil recruitment in BCG-infected IL17RA-/- mice.

Mycobacteria-infected dendritic cells attract neutrophils that produce IL-10 and specifically shut down Th17 CD4 T cells through their IL-10 receptor.

Neutrophils participate in the control of mycobacterial infection both by directly eliminating bacilli and by interacting with macrophages and dendritic cells (DCs). Despite host defenses, slow-growing mycobacteria can persist in the host for decades, mostly inside macrophages and DCs, and eventually destroy tissues after exacerbated inflammation. IL-17A-driven neutrophil recruitment may participate in this process. We report that mouse bone marrow-derived DCs infected with live Mycobacterium bovis Bacillus Calmette-Guérin (BCG) produced large amounts of CXCL1 and CXCL2, and attracted neutrophils. After physical contact with DCs infected with live BCG, the neutrophils produced large quantities of the immunosuppressive cytokine IL-10 via the MyD88 and spleen tyrosine kinase pathways. The CD11b integrin was involved in this neutrophil-DC interaction and allowed IL-10 production. TCR OVA transgenic mice immunized with a BCG strain producing OVA mounted an OVA-specific Th17 and Th1 CD4 response. Interestingly, IL-10-producing neutrophils specifically shut down IL-17A production by Th17 CD4 cells, but not IFN-γ production by Th1 cells. This was due to Th17 CD4 cell-restricted expression of the receptor for IL-10. After neutrophil depletion, total mouse lung cells produced less IL-10 but more IL-17A; IFN-γ production was not affected. Therefore, we suggest that during mycobacterial infection, regulatory neutrophils are instructed by infected reservoir DCs to produce IL-10 that specifically targets IL-10Rα-expressing Th17 CD4 T cells. This could be important to control the otherwise exuberant Th17 response.