Interferon-Gamma Fosters a Shift from Acute to Chronic Inflammation in Lyme Disease

Abstract

Borrelia burgdorferi is an extracellular bacterium that causes Lyme disease, an inflammatory, multi-systemic ailment. Interferon-γ (IFNγ) is present in lesions of human Lyme disease and positively correlates with severity of illness. Endothelial cells, which line the vasculature, mediate recruitment of immune cells to sites of infection and inflammation. To determine whether IFNγ contributes to development of Lyme disease through its actions on endothelium, cultured human umbilical vein endothelial cells (HUVEC) were exposed to B. burgdorferi, IFNγ, or the two stimuli together. Treatment of HUVEC with both stimuli enhanced the transendothelial migration of monocytes and diminished that of natural killer cells, compared to each stimulus alone. Adhesion molecules on endothelium are integral to guiding movement of leukocytes into infected tissues. Concurrent stimulation of HUVEC with IFNγ and B. burgdorferi increased expression of two such adhesion molecules, compared to each stimulus singly, and caused a third to disperse from its usual junctional location. Macrophages secrete chemoattractant cytokines (chemokines) that recruit immune cells, which could contribute to accumulation of leukocytes in lesions of Lyme disease. In studies of cultured human and murine macrophages, IFNγ and B. burgdorferi synergistically induced several chemokines for T cells and monocytes, while synergistically downregulating others that attract neutrophils. To investigate the role of IFNγ in the development of Lyme carditis, wild-type and IFNγ-deficient mice were infected with B. burgdorferi. Histological analysis of infected mice revealed no difference in severity of carditis between wild-type and IFNγ-deficient mice at 14, 21, 25, and 28 days post-infection. However, a shift in the types of leukocytes within the hearts of IFNγ-deficient mice was observed at 25 days. In the absence of IFNγ, the number of neutrophils in the heart was increased, while T cells were decreased. Bacterial loads within these hearts were similar to those in wild-type mice. Thus, both in vitro and in vivo studies show that IFNγ and B. burgdorferi cooperate to enhance recruitment of monocytes and T cells, which typify chronic inflammation, and suppress that of neutrophils and natural killer cells, which accumulate during acute inflammation. These results support the hypothesis that IFNγ promotes a shift from acute to chronic inflammation in Lyme disease.