Localized Production of IL-10 Suppresses Early Inflammatory Cell Infiltration and Subsequent Development of IFN-γ–Mediated Lyme Arthritis

Abstract

IL-10 is a non-redundant inflammatory modulator that suppresses arthritis development in Borrelia burgdorferi infected mice. Infected B6 IL-10−/− mice were previously found to have a prolonged interferon-inducible response in joint tissue. Infection of B6 IL-10 reporter mice identified macrophages and CD4+ T cells as the primary sources of IL-10 in the infected joint tissue, suggesting that early local production of IL-10 dampened the pro-arthritic interferon response. Treatment of B6 IL-10−/− mice with anti-IFN-γ reduced the increase in arthritis severity and suppressed interferon-inducible transcripts to wild type levels, thereby linking dysregulation of IFN-γ to disease in the B6 IL-10−/− mouse. Arthritis in B6 IL-10−/− mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4+ T cells as sources of IFN-γ in the joint tissue of B6 IL-10−/− mice. These findings suggest the presence of a positive feedback loop in the joint tissue of infected B6 IL-10−/− mice, where production of inflammatory chemokines, infiltration of IFN-γ producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H mice, where arthritis development is linked to transient production of Type I interferon, and develops independently of IFN-γ. Due to the sustained interferon response driven by NK cells and T cells, we propose the B6 IL-10−/− mouse as a potential model to study the persistent arthritis observed in some human Lyme disease patients.

Bacterial CD1d–Restricted Glycolipids Induce IL-10 Production by Human Regulatory T Cells upon Cross-Talk with Invariant NKT Cells

“…Finally, it is also possible that the effects of Treg-derived IL-10 extend beyond the control of the iNKT cell response. This is in line with the recently described role for IL-10 in modulating the susceptibility to Borrelia-induced Lyme arthritis in mice (39).…”

Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

“…These findings add to the known immunomodulatory functions of IL-10 in the context of borrelial infection, as well as support the growing evidence that IL-17 contributes to disease. These findings were observed using infected IL-10-deficient C57BL/6 mice, which have been described recently as a viable model to investigate elements of adaptive immunity not readily observed in traditional disease models (30). This sentiment echoes our previous claims that the use of models that exhibit the full array of immune events (including T cells) involved in the development of arthritis in humans is vital for a more complete understanding of the inflammatory events associated with Lyme arthritis in humans (16,17,23).…”

“…In addition, differences in IL-10-mediated regulation of IFN-␥ accounted for the differences in arthritic severity exhibited by C3H and C57BL/6 mice (3,28). In support of this, recent findings show that IL-10 plays a particularly important role in controlling the IFN-␥-driven arthritis caused, in large part, by CD4 ϩ T cells in B. burgdorferi-infected mice (30). Our current findings suggest that IL-10 additionally exerts its anti-inflammatory effects during B. burgdorferi infection by suppressing the production of IL-17, even in the presence of IFN-␥.…”

“…In contrast, the effects of IL-10 on IL-17 production were more pronounced after 1 week of infection. Borrelial infection in the presence or absence of IL-10 may be associated with an inverse response of various inflammatory cytokines, including not only tumor necrosis factor alpha and IFN-␥ (3,4,(28)(29)(30)(46)(47)(48)(49)(50)(51) but also IL-17. If a certain threshold of immunosuppression by IL-10 is not achieved, a significant, multifaceted inflammatory response may ensue.…”

Erythema migrans: the cutaneous manifestation of Lyme disease

“…Индукция IL-17 в зоне МЭ приводит к умень-шению количества положительных эпидермальных клеток Лангерганса (CD1a), обеспечивающих «за-хват» боррелий на ранних стадиях инфекции, спо-собствуя тем самым хронизации инфекционного процесса [14]. В развитии Лайм-артрита ведущую роль традиционно ранее приписывали Th 1 -цитокинам, таким как IFN-γ, однако в ходе недавно проведенных исследований было выявлено, что OspA B. burgdorferi может участвовать в запуске ауто-иммунного воспаления и провоцировать развитие артрита через дифференциацию Th-клеток, экс-прессирующих IL-17 [26,38]. Кроме того, в исследо-вании показано, что IFN-γ не только не индуцирует синтез анти-OspA антител, но и играет важную роль в супрессии продукции антиборрелиозных антител, что может стать обоснованием разработки высоко-эффективных вакцин [32].…”