Type I and II interferons drive inflammation through STAT1 in murine macrophage activation syndrome.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287998 | GEO | 2026/01/28
REPOSITORIES: GEO
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Project description:Hemophagocytic lymphohistiocytosis is a cytokine storm syndrome characterized by the excessive activation of myeloid and T cells. In primary HLH (pHLH), disease pathophysiology is driven by CD8 T cells proliferation and IFNg production. Therefore, targeting IFNg has been a viable option for the treatment of HLH. Since many cytokines that signaling throught the JAK/STAT pathway, including IFNg, largely drive cytokine storm in HLH, we and others have demonstrated that targeting JAK1/2 with ruxolitinib is effective in ameliorating disease manifestations in pre-clinical models of HLH. Both IFNg and ruxolitinib treatments have also shown great efficacy in dampening inflammation in patients with HLH, albeit not completely. Since ruxolitinib treatment does not fully inhibit IFNg production, we sought to determine the effect of combining ruxolitinib treatment with IFNg neutralization as a treatment option in a LCMV-infected Prf1 mice. We aimed to elucidate the effects of these treatments on the main hematologic and cellular parameters of disease. Moreover, we determined the main changes in the transcriptional landscape on CD8 T cells isolated from mice infected with LCMV either untreated or treated with aIFNg, ruxolitinib, or combination treatments. We demonstrate that combination treatment was very effective in reversing anemia and thrombocytopenia, but failed to reduce splenomegaly, hypercytokinemia, and myeloid and T cell numbers compared to ruxolitinib treatment. Transcriptional analysis revealed distinct pathways targeted by aIFNg and ruxolitinib; while aIFNg was more effective in downregulating the expression of interferon gamma response genes, allograft rejection, and complement genes, ruxolitinib treated CD8 T cells displayed a reduction in expression of genes involved in reactive oxygen species, glycolysis, E2F targets, and protein secretion pathways. Therefore, this study provide novel insights on the effects of combining ruxolitinib treatment with IFNg neutralization in the treatment of primary HLH.
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Project description:Interferon-γ (IFNγ) is a key cytokine in immune activation and anti-viral responses that classically signals via JAK1/2-mediated STAT1 homodimers to drive macrophage activation. Here, we identify a non-canonical signaling component in which IFNγ also activates STAT3. Our results show that IFNγ activates STAT3 rapidly and directly through JAK1 and JAK2. We provide the first evidence that STAT3 can form heterodimers with STAT1 in this context and demonstrate that STAT3 is co-recruited to a subset of IFNγ-induced, STAT1-bound regulatory elements. While IFNγ directly activates STAT3, our results reveal that its contribution to gene regulation is limited, indicating that STAT1 easily substitutes the STAT1–STAT3 heterodimer for STAT1 homodimers when STAT3 is absent. These findings uncover STAT3 as a new unconventional player in macrophage IFNγ signaling, underscoring the complex and context-dependent nature of cytokine signaling networks.
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