Porcine intestinal mucosa-derived alkaline phosphatase as a functional modulator of neutrophil inflammation via adenosine A2AR signaling.

Neutrophils serve as pivotal effectors in the innate immune response, yet their dysregulated activation contributes to inflammatory pathologies. Intestinal alkaline phosphatase (IAP), a potential anti-inflammatory agent derived from porcine intestinal mucosa, remains poorly understood in its mechanistic role within neutrophils. This study elucidates that IAP catalyzes the sequential dephosphorylation of adenosine triphosphate (ATP) to adenosine, which activates the adenosine 2A receptor (A2AR)-dependent cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. This pathway suppresses nuclear factor-kappa B (NF-κB) activation, thereby reducing proinflammatory cytokines and mediators in murine neutrophils. Exogenous adenosine mimicked the anti-inflammatory effects of IAP, mitigating lipopolysaccharide (LPS)-induced neutrophil hyperactivation by enhancing migration resolution and attenuating phagocytic hyperactivity. In vivo experiments corroborated that adenosine alleviates systemic inflammation via A2AR signaling, as evidenced by diminished plasma TNF-α, IL-6, and CRP levels, alongside ameliorated hepatic histopathological injury. Collectively, these findings demonstrate that IAP-derived adenosine orchestrates anti-inflammatory responses through the A2AR/cAMP/PKA/NF-κB axis, highlighting its therapeutic potential in neutrophil-mediated inflammatory disorders and valorizing intestinal mucosal waste as a sustainable source of bioactive macromolecules.