Toll-like receptor 10, a new player in the arena of Lyme-associated joint inflammation

Lyme disease is caused by Borrelia burgdorferi, and in 5-10% of the B.burgdorferi-infected individuals antibiotic therapy is insufficient and persistent symptoms will develop, including Lyme arthritis (LA). LA is characterized by cartilage- and bone destruction, as well as increased concentrations of pro-inflammatory cytokines such as interleukin (IL)-1ß and IL-17. The Toll-like receptor (TLR) family is the best described family of pattern recognition receptors. TLRs play a key role in immunity; it has been demonstrated that Borrelia-induced inflammation is highly dependent on TLR2. An outsider in this family is TLR10, which shares all structural characteristics of the TLR family but differs from the other members in function. Very recently, I discovered that TLR10 stimulation dampens inflammation induced through TLR2-driven pathways. Genetic variation in immune-related genes including TLR2 can lead to differences in clinical outcome in LA. Polymorphisms in the TLR10 gene resulted in significantly higher cytokine production upon stimulation with TLR2 ligands including B.burgdorferi. Thereby, TLR10 seems the only TLR that is able to suppress other TLR family members. This has a unique importance, since over-activation in immune processes can lead to chronic inflammation, as seen in many diseases including Lyme arthritis. Although I was able to partially unravel the TLR10-mediated pathway, the broad role of TLR10 in disease pathophysiology and the mechanisms of action are largely unknown. I propose that TLR10 is the major driving force to prevent overactivation of immune responses leading to dampening of ongoing inflammation. By promoting the TLR10 inhibitory function or downstream targets of TLR10, I hypothesize that the chronic inflammation seen in Lyme patients will be ameliorated, and this phenomenon may hold also for other autoimmune- or autoinflammatory- diseases. Therefore, I want to assess the mechanism of action of TLR10 and the role of genetic and immunological factors in Lyme disease.