Innate Immunity Crosstalk with Helicobacter pylori: Pattern Recognition Receptors and Cellular Responses

Abstract

Helicobacter pylori is one of the most successful gastric pathogens that has co-existed with human for centuries. H. pylori is recognized by the host immune system through human pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), C-type lectin like receptors (CLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs), which activate downstream signaling pathways. Following bacterial recognition, the first responders of the innate immune system, including neutrophils, macrophages, and dendritic cells, eradicate the bacteria through phagocytic and inflammatory reaction. This review provides current understanding of the interaction between the innate arm of host immunity and H. pylori, by summarizing H. pylori recognition by PRRs, and the subsequent signaling pathway activation in host innate immune cells.

Keywords: CLRs; Helicobacter pylori; NLRs; RLRs; TLRs; innate immune activation; macrophages; pattern recognition receptors.

Figure 1

Activation of pattern recognition receptors (PRRs) by H. pylori. Toll-like receptors (TLRs) 2, 4, and 5 recognize different extracellular bacterial factors to mediate MyD88-dependent or -independent activation of proinflammatory cytokine secretion. TLR7/8/9 recognize ingested bacterial DNA or single-stranded RNA (ssRNA) in phagosomes for activation of type I interferons production. Transcription factors NF-ĸB, activator protein 1 (AP1), and IRF3/7 play prominent roles in transactivation of inflammatory cytokines and type I interferons. C-type lectin-like receptors (CLRs) including MINCLE also induce NF-ĸB through interaction with CARD9/BCL10/MALT1. DC-SIGN transmits signals through an unknown pathway during H. pylori infection. NOD-like receptors (NLRs) such as NOD2 activate the inflammasome complex to induce production and maturation of IL-1β and IL-18. RIG-I-like receptors (RLRs) such as retinoic acid-inducible gene I (RIG-I) are activated by 5′triphosphate (PPP) single-stranded RNA, leading to conformation change, which subsequently activates Tank-binding kinase 1 (TBK1). This, in turn, causes production of type I interferons through IRF3/7 signaling.

Figure 2

Innate immune cells interaction with H. pylori across gastric epithelial cells (GECs). Neutrophils are directly activated by bacterial antigens, including H. pylori neutrophil activating protein (HP-NAP), type IV secretion system (T4SS), and flagellin A (FlaA), or indirectly through gastric epithelial cells secretion of hepatoma-derived growth factor (HDGF). Activation may result in proinflammatory cytokines secretion (IL-8 and IL-1β) and the production of reactive oxygen species (ROS) for the clearance of bacterial load. H. pylori can inhibit cathepsin C production to dampen neutrophil activation. It can also lead to cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) expression, which enhances neutrophils phagocytic activity without bacterial killing. Macrophages can be activated by bacterial lipopolysaccharide (LPS) or by the presence of the virulence gene cag pathogenicity island (cagPAI), resulting in mixed polarization of proinflammatory (M1) with high expressions of IL-1β, IL-6, and ROS, and the anti-inflammatory (M2) macrophages. Dendritic cells process bacterial antigens that are presented to T cells for differentiation. These cells upregulate programmed death ligand 1 (PD-L1) on regulatory T cell (Treg) to increase IL-10 secretion, leading to bacterial persistence. It can also upregulate proinflammatory cytokines IL-12 and IL-23 to stimulate T helper 1 (T_H1) and 17 (T_H17) polarization, which releases high amounts of interferon-γ (IFN-γ) and IL-17.