IFN-γ and IL-17 elicit synergistic anti-mycobacterial responses by inhibiting coronin-1A retention

CD4⁺IFN-γ⁺IL-17⁺ T cells and their secreted cytokines play a critical role in the anti-mycobacterial response. However, the underlying synergistic mechanism of IFN-γ and IL-17 is little known. This study demonstrates that the downregulation of coronin-1A retention on the phagosome is a synergistic pathway for IFN-γ and IL-17 that kills Mycobacterium tuberculosis (Mtb) in macrophages. IL-17 alone does not play a role in intracellular Mtb killing but potentiates the anti-mycobactericidal pathway of IFN-γ. Co-treatment of IFN-γ/IL-17 inhibited phosphorylation of STAT3, induced LRG47 expression, and reduced retention of coronin-1A on phagosome, thereby eliciting phagolysosomal fusion and bacterial killing, which was proved through response analysis of IFN-γ/IL-17 in Mtb-infected macrophages transfected with small interfering RNA of coro1a, lrg47, or stat1. Determination of adjunctive therapeutic effect of IFN-γ, IL-17, or both with anti-mycobacterial drugs showed that the bacterial load in the tissue of mice co-treated with IFN-γ/IL-17, even at 1 ng/mL concentration each, was more rapidly reduced compared to those of IFN-γ injection or chemotherapy alone. It inhibited the re-growth after treatment termination. Our results shed new light on the synergistic mechanisms of IFN-γ/IL-17 for anti-mycobacterial responses, which might be targeted as an adjunctive chemotherapeutic method against tuberculosis.