@Article{dbt_mods_00068013,
  author = 	{Thomas-R{\"u}ddel, Daniel
		and Giamarellos-Bourboulis, Evangelos
		and Neumann, Caroline
		and Briegel, Josef
		and Roquilly, Antoine
		and Annane, Djillali
		and Wetzker, Reinhard
		and Bauer, Michael},
  title = 	{IFN$\gamma$ in human sepsis: a scoping review},
  journal = 	{Annals of Intensive Care},
  year = 	{2025},
  month = 	{Aug},
  day = 	{05},
  publisher = 	{Springer},
  address = 	{Heidelberg},
  volume = 	{15},
  number = 	{1},
  keywords = 	{Sepsis; IFN$\gamma$; Hyperinflammation; Immunosuppression; Immunosuppressive therapy; Immunostimulatory therapy},
  abstract = 	{Abstract Background The cytokine IFN$\gamma$ is released primarily by lymphocytes to initiate and orchestrate immune responses in a broad range of target cells. Whereas immune cells release inflammatory mediators and initiate antimicrobial responses when stimulated by IFN$\gamma$, parenchymal cells frequently display increased immunogenicity and incidental cell death. In addition to these well-characterized effects of IFN$\gamma$, recent studies disclose a key role of the cytokine in sepsis and organ dysfunction. Main This review summarizes current knowledge on the IFN$\gamma$ response to infection and attempts to relate the IFN$\gamma$ response to endophenotypes of sepsis in the human host. Both, excessive pro-inflammatory responses with high IFN$\gamma$ and downstream mediators, such as chemokines (CXCL9), as well as immunosuppression with low IFN$\gamma$ levels are associated with unfavorable outcomes in sepsis. Pilot studies suggested beneficial effects of recombinant IFN$\gamma$ in counteracting immunosuppression associated with low IFN$\gamma$ levels. On the other hand, IFN$\gamma$ may induce macrophages to release chemokines CXCL9, 10, and 11 to attract B and T lymphocytes to the sites of infection. Downstream induction of CXCL9 (but not of CXCL10 and 11) occurring in a subset of patients with high IFN$\gamma$ levels has been shown to correlate with the hyper-inflammatory phenotype of sepsis. Both, high- and low-expressing IFN$\gamma$ phenotypes of sepsis, might be related to nucleotide polymorphisms of the human IFN$\gamma$ gene. Conclusion Association of IFN$\gamma$ activity states with sepsis outcome renders this key regulatory protein of immunity a top candidate for theranostic interventions in a ``personalized medicine approach'' to infection and sepsis, especially when combined with additional biomarkers, such as CXCL9, reflecting or even mediating maladaptive downstream actions. Graphical Abstract},
  note = 	{Zweitver{\"o}ffentlichung},
  issn = 	{2110-5820},
  doi = 	{10.1186/s13613-025-01534-z},
  url = 	{https://www.db-thueringen.de/receive/dbt_mods_00068013},
  url = 	{https://doi.org/10.1186/s13613-025-01534-z},
  file = 	{:https://www.db-thueringen.de/servlets/MCRFileNodeServlet/dbt_derivate_00069429/13613_2025_Article_1534.pdf:PDF},
  language = 	{en}
}