Toll-like receptor 4 inhibitor TAK-242 treatment does not influence perfusion recovery in tissue ischemia.

ABSTRACT

Toll-like receptors (TLRs) are important in innate immune responses, which are crucial in collateral artery formation (arteriogenesis). TLR4⁻/⁻ mice undergoing hind limb ischemia show decreased perfusion recovery accompanied by an impaired infiltration of inflammatory cells. TLR antagonists are currently developed and tested with the objective to inhibit acute exacerbation of organ damaging immune responses. However, systemic inhibition of innate immune responses may negatively influence arteriogenesis. In this study, we evaluated if TLR4 inhibition by a potent TLR4 inhibitor (TAK-242) would negatively influence perfusion recovery in a mouse model for arteriogenesis. Whole blood from human and mouse origin was stimulated with the TLR4 ligand lipopolysaccharide following TAK-242 incubation. After stimulation, cellular TLR4 activation was measured using fluorescence-activated cell sorting and tumor necrosis factor alpha release was measured using enzyme-linked immunosorbent assay. Next, the effect of TAK-242 was tested in a mouse model for arteriogenesis on perfusion recovery. TLR4 responses measured by tumor necrosis factor alpha levels were inhibited by TAK-242 in human and mouse blood after long-term stimulation. TAK-242 attenuated TLR4 responses in vivo but did not inhibit perfusion recovery in mice. In conclusion, TAK-242 does not negatively influence perfusion recovery following hind limb ischemia despite its TLR4 inhibiting properties.