Modeling the Role of Lanthionine Synthetase C-Like 2 (LANCL2) in the Modulation of Immune Responses to Helicobacter pylori Infection

Abstract

Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

Identification of regulatory genes through global gene expression analysis of aHelicobacter pylorico-culture system

“…Historically, H. pylori-associated regulatory responses have been mainly attributed to dendritic cells by inhibition of effector T cells and promotion of regulatory T cells (Kabisch et al, 2016; Kaebisch, Mejias-Luque, Prinz, & Gerhard, 2014; Tanaka et al, 2010). Recently, macrophages have been identified as an integral component in the generation of a regulatory gastric microenvironment during this bacterial infection (Leber et al, 2016; Viladomiu et al, 2017). Applying next-generation sequencing (NGS) and bioinformatics analysis, we demonstrated that in the tightly controlled environment of an ex vivo co-culture with BMDM, H. pylori challenge drastically influence macrophage gene expression profiles.…”

“…Macrophages have been described as key immune cells in H. pylori-induced regulatory mechanisms (Leber et al, 2016). Particularly, H. pylori interacts with a specific subset of mononuclear phagocytes that generate IL-10-driven regulatory responses facilitating optimal colonization of the gastric mucosa (Viladomiu et al, 2017).…”

Helicobacter: Inflammation, immunology and vaccines

“…also showed that arginase 2 restricts M1 macrophage activation, polyamide metabolism, and ODC expression, contributing to H. pylori immune evasion . Leber et al . used computational modeling to investigate the factors important for differentiation of regulatory macrophages.…”

“…31 Hardbower et al also showed that arginase 2 restricts M1 macrophage activation, polyamide metabolism, and ODC expression, contributing to H. pylori immune evasion. 33 Leber et al 34 Helicobacter pylori interactions with dendritic cells (DCs) are important for the differentiation of Th subsets, influence the mucosal immune response, and have an impact on disease outcome. Ko et al 37 reported that H. pylori outer membrane vesicles (OMVs) are involved in controlling gastric inflammation in vivo.…”

Oral Treatment with BT-11 Ameliorates Inflammatory Bowel Disease by Enhancing Regulatory T Cell Responses in the Gut

“…approaches from a family of 3 billion novel chemical entities (12). The decision to target the LANCL2 pathway stemmed from a thorough investigation into the role of LANCL2 in inflammation, metabolic disorders, and autoimmune diseases (13)(14)(15)(16). The effects of LANCL2 activation have been linked to secondary messenger signaling (17), cellular metabolism (18,19), cell survival (20,21), and immune effects (13,14).…”