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.

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor able to recognize both damage-associated and pathogen-associated molecular patterns, and in this respect, there has been much interest in determining the scope of ligands that bind Mincle and how structural modifications to these ligands influence ensuing immune responses. In this review, we will present Mincle ligands of known chemical structure, with a focus on ligands that have been synthetically prepared, such as trehalose glycolipids, glycerol-based ligands, and 6-acylated glucose and mannose derivatives. The ability of the different classes of ligands to influence the innate, and consequently, the adaptive, immune response will be described, and where appropriate, structure–activity relationships within each class of Mincle ligands will be presented.

Introduction: Macrophages play a significant role in the progression of diseases, such as cancer, making them a target for immune‐modulating agents. Trehalose dibehenate (TDB) is known to activate M1‐like macrophages via Mincle, however, the effect of TDB on M2‐like macrophages, which are found in the tumor microenvironment, has not been studied.Methods: qRT‐PCR, flow cytometry, cytokine ELISA, and Western Blotting were used to study the effect of TDB on GM‐CSF and M‐CSF/IL‐4 derived bone marrow macrophages (BMMs) from C57BL/6 and Mincle^−/− mice.Results: TDB treatment up‐regulated M1 markers over M2 markers by GM‐CSF BMMs, whereas M‐CSF/IL‐4 BMMs down‐regulated marker gene expression overall. TDB treatment resulted in Mincle‐independent down‐regulation of CD11b, CD115, and CD206 expression by GM‐CSF macrophages and CD115 in M‐CSF/IL‐4 macrophages. GM‐CSF BMMs produced of significant levels of proinflammatory cytokines (IL‐1β, IL‐6, TNF‐α), which was Mincle‐dependent and further enhanced by LPS priming. M‐CSF BMMs produced little or no cytokines in response to TDB regardless of LPS priming. Western blot analysis confirmed that the absence of cytokine production was associated with a lack of activation of the Syk kinase pathway.Conclusion: This study illustrates that TDB has the potential to differentially regulate M1‐ and M2‐like macrophages in the tumor environment.