Borrelia burgdorferipotently activates bone marrow-derived conventional dendritic cells for production of IL-23 required for IL-17 release by T cells

Abstract

Lyme borreliosis is characterized by cellular inflammatory responses at multiple body sites. Recently, an association of interleukin-17 (IL-17) and Lyme arthritis was suggested. In this context, it is of special interest that the heterodimeric cytokine IL-23 can act on T cells and initiate the up-regulation of effector cytokines such as IL-17. To determine the role of this specific cytokine cascade for the induction of subsequently induced proinflammatory events we developed an in vitro system to investigate the IL-23-inducing capacity of Borrelia burgdorferi and the potential of the spirochete for inducing the IL-23/IL-17 axis. We used cells derived from mice deficient for IL-23 or IL-12 only or deficient for both IL-12 and IL-23 to define precisely the function of these cytokines. Experiments with bone marrow-derived dendritic cells (BMDC) identified these cells as sources for IL-23 but not for IL-12 after B. burgdorferi exposure. Subsequent investigations with T cell-depleted splenocyte fractions revealed a tight IL-23/IL-17 axis in response to the spirochetes. Monoclonal antibodies that block IL-23 showed further that BMDC-derived IL-23 was required for production of IL-17 in this experimental model. These in vitro data describing a spirochete-induced release of IL-23 may help to define IL-17-dependent inflammatory responses in the disease.

Role of Interleukin-23 (IL-23) Receptor Signaling for IL-17 Responses in Human Lyme Disease

“…It has been demonstrated that B. burgdorferi-induced IL-17 production in mice is dependent on IL-23 (19). Cells from mice lacking bioactive IL-23 (p19 deficiency) were unable to produce IL-17.…”

“…However, this group did not show a dose-dependent induction of IL-23 production by B. burgdorferi species. So far, it was demonstrated only that murine bone marrow-derived dendritic cells (BMDCs) were able to produce IL-23 after exposure to B. burgdorferi species (19). In addition, human neutrophils were able to induce IL-23 after stimulation with neutrophil-activating protein A (NapA) isolated from B. burgdorferi (9).…”

“…In vitro studies revealed that only IL-1␤ and IL-23 are essential to generate Th17 cells (6). It has been demonstrated that IL-23 plays an important role in the induction of IL-17 after cells were stimulated in vitro with B. burgdorferi (19). It is also known that transgenic mice that overexpress IL-23 are spontaneously developing autoimmune disorders.…”

Interleukin‐17 as an Effector Molecule of Innate and Acquired Immunity against Infections

“…In in vitro assay, B. burgdorferi induced IL-23 production by DC and IL-17 production by naive spleen cells (19). Since naive mouse-derived CD4 ϩ iNKT cells which lack expression of NK1.1 surface marker recognize BbGLIIc diacylglycolipid Ag from B.…”

Lyme Arthritis: Current Concepts and a Change in Paradigm

“…Furthermore, neutralization of IL-17 causes substantial reduction of collagenase activity (33), osteoclast formation (83), and production of proinflammatory cytokines (1,32,77). Moreover, B. burgdorferi (82) or its lipoproteins (75) have been shown to induce the production of IL-17. These properties make the Th17 cell subset a strong candidate for an additional route by which Lyme arthritis may be induced.…”