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bioRxiv · 10.64898/2026.01.05.697792

Second-order regulation: IFN-γ suppresses IL-17A-mediated neutrophilic inflammation.

Ravi, V. R.·Maxfield, S. H.·Niszczak, E. N.·Kim, H. Y.·Harlow, O. S.·Whitehead, K. D.·Shenoy, A. T.
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Abstract

BACKGROUNDT helper 1 (TH1) cells often accompany TH17 cells across diverse tissues in health and disease, including the lungs. However, roles for the TH1 effector cytokine, IFN-{gamma}, in TH17-driven type 3 inflammation is unclear. METHODSWe devised a reductionistic model to determine the role of IFN-{gamma} in IL-17A-driven inflammation during Streptococcus pneumoniae (Spn) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF- and IL-17A was used to mimic rapid Spn-specific, TH17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn. Co-instillation of recombinant IFN-{gamma} was used to probe the role for this TH1 cell-derived effector cytokine in anti-Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-{gamma} on type 3 inflammation in murine airways. Mice sufficient for- or lacking-IFN-{gamma} or STAT1 were used to assess the immunoregulatory functions of IFN-{gamma} in vivo. RESULTSIFN-{gamma} 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-{gamma} on type 3 inflammation. Notably, the impact of IFN-{gamma} was more striking at lower cytokine concentrations. The immunoregulatory effect of IFN-{gamma} against TH17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wildtype (WT) mice controlled lethal Spn infection, immunized IFN-{gamma} knockout mice exhibited even better Spn clearance. This heightened antimicrobial resistance, however, was accompanied by overt airway neutrophilia suggesting risk for immunopathology. CONCLUSIONSOur findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-{gamma} limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of TH17 cells with TH1 cells may represent a conserved mechanism that restrains immunopathological potential of TH17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.

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Ravi, V. R., Maxfield, S. H., Niszczak, E. N., Kim, H. Y., Harlow, O. S., Whitehead, K. D., Shenoy, A. T.. 2026-01-06. Second-order regulation: IFN-γ suppresses IL-17A-mediated neutrophilic inflammation.. https://doi.org/10.64898/2026.01.05.697792

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