| Borrelia burgdorferi stimulates a strong inflammatory response during infection of a mammalian host. Toll-like receptors (TLRs), especially TLR2/1 heterodimers which recognize bacterial lipopeptides, play the major role in the induction of the inflammatory response to B. burgdorferi. Adaptors and co-receptors that mediate this process, as well as the mechanisms by which these adaptors and coreceptors function, are still being discovered. Here we identify integrin alpha3beta 1 as a novel regulator for the recognition of bacterial lipopeptides. We demonstrate that the induction of a specific subset of cytokines is dependent upon integrin alpha3beta1-mediated endocytosis of the lipopeptides. In addition, we address an ongoing controversy regarding endosomal recognition of bacterial lipopeptides by demonstrating that TLR2/1 signals from within endosomal compartments as well as from the plasma membrane, and that downstream responses may differ depending upon receptor localization. We propose that the regulation of endosomal TLR2/1 signaling by integrin alpha 3beta1 serves as a mechanism for modulating inflammatory responses. This inflammatory response is important for the control and clearance of the infection, but if left unchecked, inflammation damages the host tissue and causes the clinical manifestations of Lyme disease including neuroborreliosis, carditis, or arthritis. To understand the mechanisms of immune regulation employed by the host to control this inflammatory response, we focused additional studies on adrenomedullin, a peptide produced in response to bacterial stimuli that regulates inflammatory responses by modulating the expression of inflammatory cytokines. Specifically, we investigated the effect of B. burgdorferi on the expression of adrenomedullin in vitro and in vivo, as well as the ability of adrenomedullin to dampen host inflammatory responses to the spirochete. Our results suggest that B. burgdorferi increases the production of adrenomedullin, which in turn negatively regulates the B. burgdorferi-stimulated inflammatory response. These data identify a novel mechanism by which the host regulates the response to B. burgdorferi.. |
