<i>Helicobacter pylori</i> metabolites exacerbate gastritis through C-type lectin receptors
Masahiro Nagata, Kenji Toyonaga, Eri Ishikawa, Shojiro Haji, Nobuyuki Okahashi, Masatomo Takahashi, Yoshihiro Izumi, Akihiro Imamura, Koichi Takato, Hideharu Ishida, Shigenori Nagai, Petr A. Illarionov, Bridget L. Stocker, Mattie S. M. Timmer, D. Smith, Spencer J. Williams, Takeshi Bamba, Tomofumi Miyamoto, Makoto Arita, Ben J. Appelmelk, Sho Yamasaki
Abstract
Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori-specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori-specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori-specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.