bioRxiv : the preprint server for biology · 2026
Second-order regulation: IFN-γ suppresses IL-17A-mediated neutrophilic inflammation.
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Ravi Vijay Raaj, Maxfield Sophia H, Niszczak Emma N, Kim Hannah Y, Harlow Olivia S, Whitehead Kalyn D, Shenoy Anukul T
Аннотация
BACKGROUND: T helper 1 (T H 1) cells often accompany T H 17 cells across diverse tissues in health and disease, including the lungs. However, roles for the T H 1 effector cytokine, IFN-γ, in T H 17-driven type 3 inflammation is unclear.
METHODS: We devised a reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during Streptococcus pneumoniae ( Spn ) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-α and IL-17A was used to mimic rapid Spn -specific, T H 17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn . Co-instillation of recombinant IFN-γ was used to probe the role for this T H 1 cell-derived effector cytokine in anti- Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-γ on type 3 inflammation in murine airways. Mice sufficient for- or lacking-IFN-γ or STAT1 were used to assess the immunoregulatory functions of IFN-γ in vivo .
RESULTS: IFN-γ promptly muted IL-17A-induced inflammatory cell accumulation in Spn -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-γ on type 3 inflammation. Notably, the impact of IFN-γ was more striking at lower cytokine concentrations. The immunoregulatory effect of IFN-γ against T H 17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wildtype (WT) mice controlled lethal Spn infection, immunized IFN-γ knockout mice exhibited even better Spn clearance. This heightened antimicrobial resistance, however, was accompanied by overt airway neutrophilia suggesting risk for immunopathology.
CONCLUSIONS: Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-γ limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of T H 17 cells with T H 1 cells may represent a conserved mechanism that restrains immunopathological potential of T H 17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.
METHODS: We devised a reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during Streptococcus pneumoniae ( Spn ) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-α and IL-17A was used to mimic rapid Spn -specific, T H 17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn . Co-instillation of recombinant IFN-γ was used to probe the role for this T H 1 cell-derived effector cytokine in anti- Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-γ on type 3 inflammation in murine airways. Mice sufficient for- or lacking-IFN-γ or STAT1 were used to assess the immunoregulatory functions of IFN-γ in vivo .
RESULTS: IFN-γ promptly muted IL-17A-induced inflammatory cell accumulation in Spn -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-γ on type 3 inflammation. Notably, the impact of IFN-γ was more striking at lower cytokine concentrations. The immunoregulatory effect of IFN-γ against T H 17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wildtype (WT) mice controlled lethal Spn infection, immunized IFN-γ knockout mice exhibited even better Spn clearance. This heightened antimicrobial resistance, however, was accompanied by overt airway neutrophilia suggesting risk for immunopathology.
CONCLUSIONS: Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-γ limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of T H 17 cells with T H 1 cells may represent a conserved mechanism that restrains immunopathological potential of T H 17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.