Longistatin in tick saliva blocks advanced glycation end-product receptor activation.
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.
Anisuzzaman
Takeshi
T
Hatta
Takeharu
T
Miyoshi
Makoto
M
Matsubayashi
M Khyrul
MK
Islam
M Abdul
MA
Alim
M Abu
MA
Anas
M Mehedi
MM
Hasan
Yasunobu
Y
Matsumoto
Yasuhiko
Y
Yamamoto
Hiroshi
H
Yamamoto
Kozo
K
Fujisaki
Naotoshi
N
Tsuji
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012463:Saliva; D012471:Salivary Proteins and Peptides / Q000737:chemistry*; D013987:Ticks
D002135:Calcium-Binding Proteins; D008024:Ligands; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012471:Salivary Proteins and Peptides; C559189:longistatin protein, Haemaphysalis longicornis; D002118:Calcium