Ly6G⁺ granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

Area of Science:

• Immunology
• Microbiology
• Tuberculosis Research

Background:

• The immune response to Mycobacterium tuberculosis (Mtb) is complex and protective correlates are not fully understood.
• Ly6G+ granulocytes (Ly6G+Gra), IL-17, and COX2 are implicated in host-pathogen interactions during Mtb infection.

Purpose of the Study:

• To elucidate the role of the IL-17-COX2-Ly6G+Gra axis in Mtb pathogenesis.
• To investigate this axis as a potential therapeutic target for tuberculosis (TB).

Main Methods:

• Studies were conducted in Mtb-infected wild-type and Ifng-/- mice.
• Interventions included anti-IL-17 monoclonal antibody (mAb) neutralization, celecoxib (COX2 inhibitor), and RORγt inhibition.
• Analysis involved assessing Ly6G+Gra infiltration, bacterial burden, pathology, and IL-17 levels.
• Human patient data correlating neutrophil counts and IL-17 with treatment outcomes were analyzed.

Main Results:

• Ly6G+Gra harbor intracellular Mtb in infected mice.
• In Ifng-/- mice, excessive Ly6G+Gra infiltration correlated with severe disease; IL-17 neutralization and COX2 inhibition improved outcomes.
• Ly6G+Gra are a major source of IL-17 in Mtb-infected lungs.
• Inhibition of IL-17, COX2, or RORγt reduced bacterial burden within Ly6G+Gra and improved lung pathology in WT mice.
• COX2 inhibition enhanced BCG vaccine efficacy by targeting Ly6G+Gra-resident Mtb.
• In pulmonary TB patients, high neutrophil counts and IL-17 levels correlated with adverse treatment outcomes.

Conclusions:

• The IL-17-COX2-Ly6G+Gra axis represents a pro-pathogenic pathway in Mtb infection.
• IL-17 and COX2 act as negative correlates of protection.
• Targeting this axis offers a promising strategy for TB prevention and therapy.