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Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation
Vijay Raaj Ravi1, Sophia H Maxfield1, Emma N Niszczak1
1Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.
Frontiers in Immunology
|May 27, 2026
Summary
Interferon-gamma (IFN-γ) limits IL-17A-driven inflammation via STAT1, reducing airway neutrophilia during Streptococcus pneumoniae infection. While IFN-γ aids bacterial clearance, its absence increases immunopathology risk.
Area of Science:
- Immunology
- Respiratory Medicine
Background:
- T helper 1 (TH1) cells and TH17 cells coexist in various tissues, including the lungs.
- The role of TH1 effector cytokine IFN-γ in TH17-driven type 3 inflammation remains unclear.
Purpose of the Study:
- To investigate the role of IFN-γ in IL-17A-driven inflammation during *Streptococcus pneumoniae* (*Spn*) infection in a murine model.
- To elucidate the mechanism by which IFN-γ regulates type 3 inflammation in the airways.
Main Methods:
- A reductionistic model using intratracheal instillation of *Spn*, TNF-α, IL-17A, and IFN-γ in mice.
- Assessment of immune cellularity in bronchoalveolar lavage (BAL) fluid.
- Utilized mice deficient in IFN-γ or STAT1 to evaluate IFN-γ's immunoregulatory functions.
Main Results:
- IFN-γ suppressed IL-17A-induced inflammatory cell accumulation in *Spn*-infected airways via a STAT1-dependent pathway.
- IFN-γ exhibited anti-inflammatory effects in both male and female mice, more pronounced at lower cytokine concentrations.
- IFN-γ knockout mice showed enhanced *Spn* clearance but increased airway neutrophilia, suggesting immunopathology risk.
Conclusions:
- IFN-γ limits IL-17A-mediated type 3 inflammation in non-lymphoid tissues through STAT1 signaling.
- The co-occurrence of TH1 and TH17 cells may represent a conserved mechanism to control TH17-driven neutrophilic inflammation and its pathological potential.
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