Enhancement of TLR-Mediated Innate Immune Responses by Peptidoglycans through NOD Signaling

Abstract

Toll-like receptors (TLRs) recognize common motifs, pathogen-associated molecular patterns (PAMPs), in microorganisms. Bacterial PAMPs are mainly distributed on cell-surfaces. Peptidoglycans (PGNs) are ubiquitous constituents of bacterial cell walls. Muramyldipeptide (MDP; N-acetylmuramyl-l-alanyl-d-isoglutamine) is a common and key structure of PGNs and exhibits most the of bioactivities of PGNs. Recently, the intracellular receptor for MDP was revealed to be NOD2. Another bioactive moiety of PGNs, diaminopimelic acid (DAP) containing desmuramylpeptides (DMPs), senses another intracellular receptor, NOD1. MDP-primed mice exhibited hyper-responses to endotoxin and other bacterial components, which sense Toll-like receptors (TLRs), although MDP itself does not exhibit apparent activity in mice. On the other hand, DMPs exhibited definite activity in mice, and the most powerful DMP, FK565, exhibited stronger priming activity than MDP. In human monocytic cells, both MDP and DMPs exhibited definite activities; marked synergistic interleukin (IL)-8 secretion was induced by DMPs and MDP in combination with synthetic TLR agonists, and suppression of the mRNA expressions of NOD1 and NOD2, respectively, by RNA interference specifically inhibited synergistic IL-8 secretion. In human dendritic cells (DCs), synergistic T helper type 1 responses are induced by combined stimulations of synthetic NOD and TLR agonists. Considering these findings altogether, in host-bacteria interactions, host cells should recognize bacteria via both TLRs and NODs, which might induce synergistic innate and adaptive immune responses.

Cutting Edge: New Chimeric NOD2/TLR2 Adjuvant Drastically Increases Vaccine Immunogenicity

“…Consistent with the knowledge that TLR2 and NOD2 pathways act synergistically on human B lymphocytes (28) and DCs (29) to induce immune responses, as well as our in vitro data, the strong adjuvant effect observed in vivo is probably due to the induction of inflammation at the injection site, which leads to the recruitment of APCs such as macrophages and DCs. The latter are able to uptake Ag carried by PLA NPs and then migrate to draining lymph nodes to present Ag to naive T cells.…”

Pattern Recognition Receptor-Dependent Mechanisms of Acute Lung Injury

“…NOD1 senses diaminopimelic acid-containing peptidoglycan present in Gram-negative bacteria, whereas NOD2 senses the muramyl dipeptide present in most organisms. Because of the apparent lack of direct effects on cell signaling induced by activators of NLRs, it is suggested that their role in pathogen sensing is one of cooperation with the TLRs (107). However, studies suggested that the actions of NOD1 vary between cell types and, unlike those seen with LPS, the in vivo effects may be independent of leukocyte activation.…”

Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

“…Synthetic NOD1 agonists stimulate chemokine production and neutrophil recruitment in vivo (Masumoto et al 2006), but alone are ineffective in activating monocytic cells in vitro (van Heel et al 2005). Because of the apparent lack of direct effects on cell signalling induced by activators of NLRs, it is suggested that their role in pathogen sensing is one of co-operation with the TLRs (Takada & Uehara 2006). However, data from our group suggest that the actions of NOD1 vary between cell types and, unlike those seen with LPS, the in vivo effects may be independent of leukocyte activation.…”