Local Production of IFN-γ by Invariant NKT Cells Modulates Acute Lyme Carditis

Abstract

The Lyme disease spirochete Borrelia burgdorferi is the only known human pathogen that directly activates invariant NKT (iNKT) cells. The number and activation kinetics of iNKT cells vary greatly among different strains of mice. We now report the role of the iNKT cell response in the pathogenesis of Lyme disease using C57BL/6 mice, a strain with optimal iNKT cell activation that is resistant to the development of spirochetal-induced inflammation. During experimental infection of B6 mice with B. burgdorferi, iNKT cells localize to the inflamed heart where they are activated by CD1d-expressing macrophages. Activation of iNKT cells in vivo results in the production of IFN-γ, which we demonstrate ameliorates the severity of murine Lyme carditis by at least two mechanisms. First, IFN-γ enhances the recognition of B. burgdorferi by macrophages, leading to increased phagocytosis of the spirochete. Second, IFN-γ activation of macrophages increases the surface expression of CD1d, thereby facilitating further iNKT activation. Collectively, our data demonstrate that in the resistant background, B6, iNKT cells modulate the severity of murine Lyme carditis through the action of IFN-γ, which appears to self-renew through a positive feedback loop during infection.

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

“…Bone marrow-derived macrophages were generated as described in ref. 2 and SI Materials and Methods. CHO cells transfected with human CR3, CD14, or CR4 were maintained in Ham's F-12 medium (Sigma Chemical).…”

“…CD11b-deficient mice and wild-type littermates were infected with B. burgdorferi as described in ref. 2. The mice were killed at the peak of infection and analyzed for inflammation, bacterial burdens, and tnf gene expression levels in the heart (SI Materials and Methods).…”

“…If not eradicated with appropriate antimicrobial therapy, the spirochete can disseminate hematogenously and invade target organs, giving rise to clinical manifestations such as carditis, meningitis, and acute arthritis (1). 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). Phagocytosis, in turn, leads to the production of proinflammatory factors that contribute to tissue damage (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). Phagocytosis, in turn, leads to the production of proinflammatory factors that contribute to tissue damage (2).…”