Periodic Reporting for period 1 - CYTOMAC (Cytokine signaling in macrophages: beyond JAK-STAT)
Periodo di rendicontazione: 2023-09-01 al 2026-02-28
CYTOMAC explores how cytokines with opposing functions produce distinct macrophage responses despite engaging similar JAK-STAT signaling pathways. The project aims to identify transcription factors that cooperate with JAK-STAT to drive cytokine-specific enhancer activation.
Using genetic variation, enhancer mapping, and multi-omics profiling in mouse and human macrophages, we established all core pipelines and identified a new transcription factor regulating cytokine gene responses. Also, we uncovered a non-canonical IFNγ–STAT3 signaling branch.
CYTOMAC uncovered a previously unknown non-canonical IFNγ–STAT3 signaling branch in macrophages, demonstrating direct STAT3 activation and redefining classical JAK-STAT signaling models. Through genetic-variation–based enhancer mapping, we identified a transcription-factor family as key regulator of cytokine-specific enhancer activation. Together, these results will help explain how cytokine specificity arises despite shared signaling components. These findings may open avenues for cytokine-selective anti-inflammatory strategies that minimize the broad immunosuppressive effects of current JAK inhibitors.