二级调控：IFN-γ抑制IL-17A介导的3型炎症
Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation.
摘要(中文译文)
辅助性T细胞1（T1）在健康和疾病状态下常与T17细胞共同存在于多种组织中，包括肺部。然而，T1效应细胞因子IFN-γ在T17驱动的3型炎症中的作用尚不明确。我们设计了一个简化的还原论模型，以确定IFN-γ在（）感染期间IL-17A驱动的炎症中的作用。简言之，采用气管内滴注（）联合重组TNF-α和IL-17A来模拟肺部在记忆 recall 感染（）后出现的快速特异性、T17驱动的3型炎症。通过共滴注重组IFN-γ来探究这一T1细胞来源的效应细胞因子在抗免疫应答中的作用。以支气管肺泡灌洗液（BAL）中的免疫细胞构成来判定IFN-γ对小鼠气道3型炎症的影响。使用IFN-γ充足或缺失、或STAT1充足或缺失的小鼠来评估IFN-γ的免疫调节功能。IFN-γ通过STAT1依赖机制迅速抑制了感染气道中IL-17A诱导的炎症细胞聚集。雌性和雄性小鼠均表现出IFN-γ对3型炎症相似的抗炎效应。我们发现IFN-γ的影响取决于3型炎症的程度，即在三种细胞因子浓度均较低时，IFN-γ的免疫调节作用更为显著。值得注意的是，IFN-γ对T17驱动的3型炎症的免疫调节效应在生理相关环境中同样明显：免疫的野生型（WT）小鼠可控制致死性感染，而免疫的IFN-γ敲除小鼠表现出更好的清除能力。然而，这种改善的抗微生物抵抗力伴随着气道中性粒细胞增多的加剧（仅在中和免疫野生型小鼠中的IFN-γ即可复制此表型），提示存在免疫病理风险。我们的研究结果揭示了一种在非淋巴组织中运作的独特免疫调节机制，其中IFN-γ通过STAT1限制IL-17A介导的3型炎症。因此，T17细胞与T1细胞的频繁伴随可能代表一种保守机制，通过非淋巴组织中的STAT1信号传导来约束T17驱动的中性粒细胞性炎症的免疫病理潜能。
Abstract
T helper 1 (T1) cells often accompany T17 cells across diverse tissues in health and disease, including the lungs. However, roles for the T1 effector cytokine, IFN-γ, in T17-driven type 3 inflammation is unclear. We devised a simplified reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during () infection Briefly, intratracheal instillation of along with recombinant TNF-α and IL-17A was used to mimic rapid -specific, T17-driven, type 3 inflammation seen in lungs on memory recall infection with . Co-instillation of recombinant IFN-γ was used to probe the role for this T1 cell-derived effector cytokine in anti- 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 IFN-γ promptly muted IL-17A-induced inflammatory cell accumulation in -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-γ on type 3 inflammation. We find that the impact of IFN-γ was dependent on the degree of type 3 inflammation such that IFN-γ's immunoregulatory role became more striking at lower concentrations of all the three cytokines. Of note, the immunoregulatory effect of IFN-γ against T17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wild type (WT) mice controlled lethal infection, immunized IFN-γ knockout mice exhibited even better clearance. This improved antimicrobial resistance, however, was accompanied by heightened airway neutrophilia (which could be phenocopied by mere neutralization of IFN-γ in immunized wild type mice) suggesting risk for immunopathology. 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 T17 cells with T1 cells may represent a conserved mechanism that restrains immunopathological potential of T17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.
如何引用
AMA
Vijay Raaj Ravi, Sophia H Maxfield, Emma N Niszczak, Hannah Y Kim, Olivia S Harlow, Anjali Kakarla, et al. Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1744476.
APA
Vijay Raaj Ravi, Sophia H Maxfield, Emma N Niszczak, Hannah Y Kim, Olivia S Harlow, Anjali Kakarla, et al (2026). Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1744476
GB/T 7714
Vijay Raaj Ravi, Sophia H Maxfield, Emma N Niszczak, Hannah Y Kim, Olivia S Harlow, Anjali Kakarla, et al. Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1744476.
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