Uncovering an unconventional JAK1/2-STAT3 branch in macrophage IFNγ signaling

Interferon-{gamma} (IFN{gamma}) is a key cytokine in immune activation, especially anti-viral responses and driver of macrophage activation. It classically signals via JAK1/2-mediated STAT1 homodimers. Here, we identify an alternative, non-canonical signaling component in which IFN{gamma} simultaneously also activates STAT3. Our results show that IFN{gamma} 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 IFN{gamma}-induced, STAT1-bound regulatory elements. While IFN{gamma} 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 IFN{gamma} signaling, underscoring the complex and context-dependent nature of cytokine signaling networks.