Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Abstract

Lyme arthritis, caused by the spirochete Borrelia burgdorferi, can be recurrent or prolonged, whereas Lyme carditis is mostly nonrecurring. A prominent difference between arthritis and carditis is the differential representation of phagocytes in these lesions: polymorphonuclear leukocytes (PMN) are more prevalent in the joint, and macrophages predominate in the heart lesion. We have previously shown differential efficiency of B. burgdorferi clearance by PMN and macrophages, and we now investigate whether these functional differences at the cellular level may contribute to the observed differences in organ-specific pathogenesis. When we infected mice lacking the neutrophil chemokine receptor (CXCR2 ؊/؊ mice) with spirochetes, we detected fewer PMN in joints and less-severe arthritis. Here we have investigated the effects of the absence of the macrophage chemokine receptor CCR2 on the development and resolution of Lyme carditis in resistant (C57BL/6J [B6]) and sensitive (C3H/HeJ [C3H]) strains of mice. In B6 CCR2؊/؊ mice, although inflammation in hearts is mild, we detected an increased burden of B. burgdorferi compared to that in wild-type (WT) mice, suggesting reduced clearance in the absence of macrophages. In contrast, C3H CCR2 ؊/؊ mice have severe inflammation but a decreased B. burgdorferi burden compared to that in WT C3H mice both at peak disease and during resolution. Histopathologic examination of infected hearts revealed that infected C3H CCR2؊/؊ animals have an increased presence of PMN, suggesting compensatory mechanisms of B. burgdorferi clearance in the hearts of infected C3H CCR2 ؊/؊ mice. The more efficient clearance of B. burgdorferi from hearts by CCR2 ؊/؊ versus WT C3H mice suggests a natural defect in the recruitment or function of macrophages in C3H mice, which may contribute to the sensitivity of this strain to B. burgdorferi infection.

CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis ofBorrelia burgdorferi

“…In particular, macrophages are critical components of the response to B. burgdorferi, particularly during skin and cardiac infection (3). Macrophages phagocytose spirochetes, contributing to their elimination from infected tissues (2,3). Phagocytosis, in turn, leads to the production of proinflammatory factors that contribute to tissue damage (2).…”

“…It is generally believed that the pathology associated with infection results from the activation of locally recruited immune cells and the ensuing inflammatory response (2). In particular, macrophages are critical components of the response to B. burgdorferi, particularly during skin and cardiac infection (3). Macrophages phagocytose spirochetes, contributing to their elimination from infected tissues (2,3).…”

Recognition of Borrelia burgdorferi, the Lyme Disease Spirochete, by TLR7 and TLR9 Induces a Type I IFN Response by Human Immune Cells

“…Phagocytic cells of the innate immune system, which can include monocytes/ macrophages, dendritic cells, and neutrophils, infiltrate the EM lesion of patients and the infected joints and cardiac tissue of susceptible mouse strains (2)(3)(4)(5)(6). Interaction of these phagocytes with B. burgdorferi can control spirochete burden in infected tissues but simultaneously elicit an array of inflammatory cytokines, which contribute to Lyme disease pathogenesis (7,8).…”

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

“…Neutrophils are the principal cell type that controls clearance of Borrelia in infected joints. [3][4][5] Thus, to understand whether the higher spirochetal load in the joints of CD14 Ϫ/Ϫ mice is due to a lack of or diminished neutrophil recruitment, we used MPO staining to quantify the neutrophil content in tibiotarsal joints from infected animals. MPO, a lysosomal protein stored in azurophilic granules, serves as an ideal and specific marker for tracking the migration of neutrophils into inflamed tissues.…”

“…Neutrophils are the principal early infiltrating cell type observed in the infected joints of humans, 2 a finding mirrored in a mouse model of Lyme arthritis. [3][4][5][6] Depletion of neutrophils results in early onset of arthritis with a higher bacterial burden in murine Lyme borreliosis. 4 Conversely, B. burgdorferi genetically engineered to express KC (the murine equivalent of human CXCL8), a neutrophil-recruiting chemokine, is rapidly cleared from mouse tissues because of a faster and continuous influx of neutrophils to the site of infection.…”