Role of Adrenomedullin in Lyme Disease

Abstract

Borrelia burgdorferi stimulates a strong inflammatory response during infection of a mammalian host. To understand the mechanisms of immune regulation employed by the host to control this inflammatory response, we focused our studies on adrenomedullin, a peptide produced in response to bacterial stimuli that exhibits antimicrobial activity and regulates inflammatory responses by modulating the expression of inflammatory cytokines. Specifically, we investigated the effect of B. burgdorferi on the expression of adrenomedullin as well as the ability of adrenomedullin to dampen host inflammatory responses to the spirochete. The concentration of adrenomedullin in the synovial fluid of untreated Lyme arthritis patients was elevated compared with that in control osteoarthritis patient samples. In addition, coculture with B. burgdorferi significantly increased the expression of adrenomedullin in RAW264.7 macrophages through MyD88-, phosphatidylinositol 3-kinase (PI3-K)-, and p38-dependent signaling cascades. Furthermore, the addition of exogenous adrenomedullin to B. burgdorferi-stimulated RAW264.7 macrophages resulted in a significant decrease in the induction of proinflammatory cytokines. Taken together, these results suggest that B. burgdorferi increases the production of adrenomedullin, which in turn negatively regulates the B. burgdorferi-stimulated inflammatory response.Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne disease in the United States. During infection of a mammalian host, B. burgdorferi disseminates from the site of entry to colonize distal tissues throughout the body, including the nervous system, heart, and joints. In each of these sites, the interaction of B. burgdorferi with the host results in the induction of an inflammatory response. 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 avoid an overexuberant and potentially damaging inflammatory response, host cells employ multiple mechanisms for controlling inflammation.Adrenomedullin is a host factor that negatively regulates inflammation. It is expressed by numerous cells as a preproadrenomedullin peptide, which is further processed to yield two mature and active peptides, proadrenomedullin N-terminal 20 peptide (PAMP) and the 52-amino-acid adrenomedullin (34). Adrenomedullin is constitutively secreted from cells in its immature form (26, 51) and is activated after secretion by amidation of its C terminus (33).Adrenomedullin expression is induced by several bacterial pathogens (3,30,57) and by inflammatory environments (22,23,36,53). Adrenomedullin possesses immunomodulatory activities which have been demonstrated to downregulate inflammatory processes in a variety of different models, including models of arthritis. For example, the administration of exogenous adrenomedullin protects mice from arthr...

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“…Borrelia burgdorferi, which causes Lyme disease, has been shown to induce adrenomedullin expression in the synovial fluid of untreated Lyme arthritis patients compared with control osteoarthritis patients (Marre et al 2010), possibly in an attempt to block the progression of the disease.…”