Longistatin in tick saliva blocks advanced glycation end-product receptor activation

Authors:
  • AAA Anisuzzaman
    A Anisuzzaman
  • THTakeshi Hatta
    Takeshi Hatta
  • TMTakeharu Miyoshi
    Takeharu Miyoshi
  • MMMakoto Matsubayashi
    Makoto Matsubayashi
  • MIM. Khyrul Islam
    M. Khyrul Islam
  • MAM. Abdul Alim
    M. Abdul Alim
  • MAM. Abu Anas
    M. Abu Anas
  • MHM. Mehedi Hasan
    M. Mehedi Hasan
  • YMYasunobu Matsumoto
    Yasunobu Matsumoto
  • YYYasuhiko Yamamoto
    Yasuhiko Yamamoto
  • HYHiroshi Yamamoto
    Hiroshi Yamamoto
  • KFKozo Fujisaki
    Kozo Fujisaki
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Abstract
Ticks are notorious hematophagous ectoparasites and vectors of many deadly pathogens. As an effective vector, ticks must break the strong barrier provided by the skin of their host during feeding, and their saliva contains a complex mixture of bioactive molecules that paralyze host defenses. The receptor for advanced glycation end products (RAGE) mediates immune cell activation at inflammatory sites and is constitutively and highly expressed in skin. Here, we demonstrate that longistatin secreted with saliva of the tick Haemaphysalis longicornis binds RAGE and modulates the host immune response. Similar to other RAGE ligands, longistatin specifically bound the RAGE V domain, and stimulated cultured HUVECs adhered to a longistatin-coated surface; this binding was dramatically inhibited by soluble RAGE or RAGE siRNA. Treatment of HUVECs with longistatin prior to stimulation substantially attenuated cellular oxidative stress and prevented NF-κB translocation, thereby reducing adhesion molecule and cytokine production. Recombinant longistatin inhibited RAGE-mediated migration of mouse peritoneal resident cells (mPRCs) and ameliorated inflammation in mouse footpad edema and pneumonia models. Importantly, tick bite upregulated RAGE ligands in skin, and endogenous longistatin attenuated RAGE-mediated inflammation during tick feeding. Our results suggest that longistatin is a RAGE antagonist that suppresses tick bite–associated inflammation, allowing successful blood-meal acquisition from hosts.

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