Recognition ofBorrelia burgdorferiby NOD2 Is Central for the Induction of an Inflammatory Reaction

Abstract

Toll-like receptor 2 (TLR2) plays an important role in the recognition of Borrelia bacteria, the causative agent of Lyme disease, but the existence and importance of additional receptors in this process has been hypothesized. In the present study, we confirmed the role played by TLR2 in the recognition of Borrelia bacteria but also demonstrated a crucial role for the intracellular peptidoglycan receptor NOD2 for sensing the spirochete. Cells from individuals who were homozygous for the loss-of-function mutation 3020insC in the NOD2 gene were defective with respect to cytokine release after stimulation with Borrelia species, and this was confirmed in peritoneal macrophages from mice lacking RICK, the adaptor molecule used by NOD2. In contrast, NOD1 played no major role in the recognition of Borrelia spirochetes. This raises the intriguing possibility that recognition of Borrelia spirochetes is exerted by TLR2 in combination with NOD2 and that both receptors are necessary for an effective induction of cytokines by Borrelia species. The interplay between TLR2 and NOD2 might not only be necessary for the induction of a proper immune response but may also contribute to inflammatory-induced pathology.

Interleukin-10 Alters Effector Functions of Multiple Genes Induced by Borrelia burgdorferi in Macrophages To Regulate Lyme Disease Inflammation

“…burgdorferi triggers the production of inflammatory mediators in macrophages via recognition of both Toll-like receptors (TLRs) and non-TLRs (8,12,22,71,78,95,97). In the present study, gene array analysis identified candidate genes from multiple pathways induced by live spirochetes that were a A corrected one-way analysis of variance was used to analyze the microarray data.…”

Role of Interleukin-23 (IL-23) Receptor Signaling for IL-17 Responses in Human Lyme Disease

“…Of interest, proinflammatory cytokine interleukin-1␤ (IL-1␤) is essential for the development of Th17 responses, and B. burgdorferi is a potent inducer of IL-1␤ (25). Recently, it was also demonstrated that caspase-1 is crucial for B. burgdorferiinduced IL-17 responses (26).…”

Autophagy Modulates Borrelia burgdorferi-induced Production of Interleukin-1β (IL-1β)

“…Several in vitro studies indicate the importance of lipid-modified proteins in the pathogenesis of the infection (6 -8). The immune system recognizes these lipoproteins by different pattern recognition receptors, of which Tolllike receptor 2 (TLR2) 5 and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are suggested to be the most important (4,9). The activation of pattern recognition receptors after recognition of Borrelia results in the secretion of the proinflammatory cytokine IL-1␤ which is known to be involved in the pathogenesis of Lyme disease (10 -12).…”