Deciphering the association between Sirt2 modulation and non-canonical Wnt/planar cell polarity-dependent splenic...

Enhancement of the splenic function by preserving its cellular/junctional integrity is an underrated effective strategy in combatting infections. The present work aimed to assess the effect of sirtuin (Sirt) modulation in splenic dysfunction associated with lipopolysaccharide (LPS)-induced endotoxemia in rats. Endotoxemia was induced by a single LPS injection (10 mg/kg; i.p) either solely or preceded by one of 2 Sirt modulators for 3 days; AGK2 (41 mg/kg/d; i.p) or resveratrol (RSV; 40 mg/kg/d; i.p). The results revealed an existing association between AGK2-mediated Sirt-2 inhibition and wingless homolog Wnt5a refining with contemporaneous stimulation of the splenic receptor tyrosine kinase like orphan receptor-2/Frizzled-4/Dishevelled-2 axis. This coincided with enhancement of the planar cell polarity stream (PCP) components, namely, Guanosine-5'-triphosphate-bound Ras homolog family member-A/rho-associated coil-containing protein kinase-1/2, that was in turn linked to augmentation of splenic VE-cadherin content and immunohistochemical expression and instigation of focal adhesion kinase activating phosphorylation. These events were accompanied by enhanced splenic count of differentiated T cells to halt the plasma endotoxin increment with partial suppression of the resultant cytokine storm. The biochemical amendment was further validated by restoration of splenic macro- and microscopic architecture, improved survival and clinical outcomes, and amelioration of end-organ damage markers. Resveratrol failed to achieve such remarkable effects; a conclusion that might be attributed to the hinderance of its anti-inflammatory actions by its Sirt-2 activating capacity, leading to eventual mild endotoxin level decrement in the experimental model. The Sirt2 selective inhibition might be superior in renovating splenic patterning by fine-tuning the Wnt5a/PCP axis and reconstructing junctional scaffolding that functions to expand the blood filtration capacity, besides, immune cells synthesis and migration, presenting a novel approach to conquer the underlying endotoxemia.