IFNγ in human sepsis: a scoping review

Abstract

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.

Keywords: Hyperinflammation; IFNγ; Immunostimulatory therapy; Immunosuppression; Immunosuppressive therapy; Sepsis.

Fig. 1

IFNγ and downstream cytokines and chemokines implicated in innate and adaptive immune responses to infection. IFNγ and several downstream cytokines and chemokines act as main players of the cooperative immune response to infection. After initial contact of tissue macrophages and resident T cells, lymphocytes release IFNγ, which boosts innate resistance responses of macrophages. These responses include secretion of the cytokine IL-12 and of chemokines, which are aimed to attract and to further stimulate lymphocytes. In a self-accelerating circuit the overall immune response further increases (ideally) until complete elimination of invading pathogens

Fig. 2

PRISMA flow diagram of selection of sources of evidence

Fig. 3

Prospects of modulation of IFNγ and its downstream signaling cascades in adjunctive therapy of sepsis. Topology of the IFNγ—chemokine signaling circuit between lymphocytes and macrophages and related treatment options for immunosuppression (blue) and hyperinflammatory (red) phenotypes of sepsis. Studies reporting use of recombinant IFNy are two case reports [37, 38] and in uncontrolled case series [11, 39, 40]. Results of a multicenter trial (ImmunoSep; NCT04990232) are currently unpublished. All other drugs have been only testet in animal experiments or preclinical settings