Borrelia burgdorferiLipoprotein–Mediated TLR2 Stimulation Causes the Down‐Regulation of TLR5 in Human Monocytes

Abstract

Toll-like receptors (TLRs) trigger innate immune responses via the recognition of conserved pathogen-associated molecular patterns. Lipoproteins from Borrelia burgdorferi the agent of Lyme disease, activate inflammatory cells through TLR2 and TLR1. We show that stimulation of human monocytes with B. burgdorferi lysate, lipidated outer surface protein A, and triacylated lipopeptide Pam3CysSerLys4 results in the up-regulation of both TLR2 and TLR1 but the down- regulation of TLR5, the receptor for bacterial flagellin, and that this effect is mediated via TLR2. TLR4 stimulation had no effect on TLR2, TLR1, and TLR5 expression. Human monocytes stimulated with TLR5 ligands (including p37 or flaA, the minor protein from B. burgdorferi flagella) up-regulated TLR5. In addition, TLR2 stimulation rendered cells hyporesponsive to a TLR5 agonist. These results indicate that diverse stimuli can cause differential TLR expression, and we hypothesize that these changes may be useful for either the pathogen and/or the host Lyme disease is a multisystem illness caused by Borrelia burgdorferi and is the most common vectorborne illness in the United States. It usually begins with erythema migrans, a characteristic rash at the inoculation site. Within several days or weeks, there is hematogenous dissemination of the spirochetes, and patients may present with dermatological, neurological, cardiac, and rheumatological involvement [1]. The mechanisms involved in eliminating the organism versus those contributing to disease and persistent infection are not yet understood. The main inflammatory response against B. burgdorferi is directed against spirochetal lipoproteins [2–4] Toll-like receptors (TLRs) are a family of pattern-recognition receptors that are important in innate immune defense. Signal transduction through TLRs activates NF-κB and the production of cytokines, chemokines, and costimulatory molecules [5]. TLR2 mediates immune responses to a broad range of microbial products and is critical for the recognition of bacterial lipopeptides. It functions in combination with TLR1 to recognize triacylated lipopeptides, such as mycobacterial lipoprotein, or the outer surface protein A (OspA) of B. burgdorferi [6, 7]. TLR5 recognizes flagellin [8], the main component of bacterial flagella, which is critically important for bacterial motility In the present study, we show that human peripheral blood mononuclear cells (PBMCs) and monocytes up-regulate TLR1 and TLR2 and down-regulate TLR5 when they are stimulated with B. burgdorferi lysate (BL), lipidated-OspA (L-OspA), and Pam3CysSerLys4 (Pam3CSK4, a synthetic lipohexapeptide that mimics the structure of the lipoprotein lipid moiety). These findings are specific for TLR2 stimulation, because TLR4 stimulation does not up-regulate TLR1 and TLR2 or down-regulate TLR5. TLR5 ligands up-regulate TLR5 but have no effect on TLR1 and TLR2. The results of our study indicate a role of the differential expression of certain TLRs durin

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