IFNγ in human sepsis: a scoping review

Overview & Synopsis

Background : The cytokine IFNγ 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 IFNγ, parenchymal cells frequently display increased immunogenicity and incidental cell death. In addition to these well-characterized effects of IFNγ, recent studies disclose a key role of the cytokine in sepsis and organ dysfunction. Main This review summarizes current knowledge on the IFNγ response to infection and attempts to relate the IFNγ response to endophenotypes of sepsis in the human host. Both, excessive pro-inflammatory responses with high IFNγ and downstream mediators, such as chemokines (CXCL9), as well as immunosuppression with low IFNγ levels are associated with unfavorable outcomes in sepsis. Pilot studies suggested beneficial effects of recombinant IFNγ in counteracting immunosuppression associated with low IFNγ levels. On the other hand, IFNγ 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 IFNγ levels has been shown to correlate with the hyper-inflammatory phenotype of sepsis. Both, high- and low-expressing IFNγ phenotypes of sepsis, might be related to nucleotide polymorphisms of the human IFNγ gene. Conclusion : Association of IFNγ 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.