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CD14 signaling reciprocally controls collagen deposition and turnover to regulate the development of lyme arthritis.

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Abstract

CD14 is a glycosylphosphatidylinositol-anchored protein expressed primarily on myeloid cells (eg, neutrophils, macrophages, and dendritic cells). CD14(-/-) mice infected with Borrelia burgdorferi, the causative agent of
Lyme disease, produce more proinflammatory cytokines and present with greater
disease and bacterial burden in infected tissues. Recently, we uncovered a novel mechanism whereby CD14(-/-) macrophages mount a hyperinflammatory response, resulting from their inability to be tolerized by B. burgdorferi. Paradoxically, CD14 deficiency is associated with greater bacterial burden despite the presence of highly activated neutrophils and macrophages and elevated levels of cytokines with potent antimicrobial activities. Killing and clearance of Borrelia, especially in the joints, depend on the recruitment of neutrophils. Neutrophils can migrate in response to chemotactic gradients established through the action of gelatinases (eg, matrix metalloproteinase 9), which degrade collagen components of the extracellular matrix to generate tripeptide fragments of proline-glycine-proline. Using a mouse model of
Lyme arthritis, we demonstrate that CD14 deficiency leads to decreased activation of matrix metalloproteinase 9, reduced degradation of collagen, and diminished recruitment of neutrophils. This reduction in neutrophil numbers is associated with greater numbers of Borrelia in infected tissues. Variation in the efficiency of neutrophil-mediated clearance of B. burgdorferi may underlie differences in the severity of
Lyme arthritis observed in the patient population and suggests avenues for development of adjunctive therapy designed to augment host immunity.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Am J Pathol. 2011 Feb;178(2):724-34. doi: 10.1016/j.ajpath.2010.10.025. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t; Research Support, U.S. Gov’t, Non-P.H.S.

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