Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors

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.

Orientia tsutsugamushi selectively stimulates the C-type lectin receptor Mincle and type 1-skewed proinflammatory immune responses

“…As an obligately intracellular pathogen, O. tsutsugamushi relies on the host cell as a source of nutrients [33]. Therefore, it is conceivable that enzymatic altering of host cell proteins or lipids during this process may, in turn, stimulate Mincle, in a similar manner to that described for Helicobacter pylori [26]. Identification of such a ligand, however, presents major challenges due to the lack of available tools for genetic manipulation of O. tsutsugamushi at the present time [7,11].…”

“…Since Mincle does not harbor an ITIM or ITAM, it relies on Fc receptor gamma (Fcgr; FcγR) to initiate immune signaling cascades [24]. While the functional significance of Mincle activation is variable in different host-pathogen interactions or diseases, Mincle signaling is known to lead to proinflammatory cytokine production, M1 MF phenotype, and a type 1-or Th17-favoring cytokine milieu [23,25,26]. To date, CLRs have been virtually unstudied in the context of obligately intracellular pathogens, and the PRR profile responding to O. tsutsugamushi remains poorly characterized.…”

Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease

“…The C-type lectin innate immune receptors (CLRs) can recognize various pathogen-related carbohydrate structures ( 76 ) but the spectrum of their role in H. pylori recognition and the extent of their involvement in gastritis development is not fully understood. CLRs have been very recently shown to be able to detect host metabolites modified by H. pylori and induce gastritis ( 77 ).…”

“…High serum values of γ-linolenic acid were associated with reduced risk for atrophic gastritis ( 81 ), and this metabolite has been considered as an anti-inflammatory and anti-proliferative agent ( 82 ). H. pylori converts host’s cholesterol into cholesteryl glucosides that has been recently shown to modulate host’s immunity and gastritis ( 77 ).…”

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer

“…These toxins subsequently contribute to the gastric mucosa damage. The long-term colonization of H. pylori in the stomach could also disrupt immune imbalance and induce inflammatory responses (8,9). Some pro-inflammatory factors can destroy the gastric mucosal barrier and promote the occurrence and development of gastrointestinal diseases (10,11).…”