Functional crosstalk between myeloid Foxo1-β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response

Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1(M-KO)) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1(M-KO) enhanced beta-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1(M-KO) livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and beta-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with beta-catenin under inflammatory conditions. Disruption of the Foxo1-beta-catenin axis by Foxo1 deletion enhanced beta-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1-beta-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.

Automated summary

The study demonstrates that myeloid-specific Foxo1 knockout mice are resistant to oxidative stress-induced liver injury by enhancing beta-catenin-mediated Gli1/Snail signaling, reducing inflammation, and inhibiting necroptosis. The colocalization of Foxo1 and beta-catenin in macrophages leads to the activation of Gli1/Snail signaling and suppression of RIPK3 and NEK7/NLRP3 expression under inflammatory conditions. Disruption of this axis exacerbates liver damage, leading to increased necroptosis and inflammatory response.