CD-14, Collagen, and Lyme

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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.