IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

Abstract

Borrelia burgdorferi is capable of persistently infecting a variety of hosts despite eliciting potent innate and adaptive immune responses. Preliminary studies indicated that IL-10-deficient (IL-10−/−) mice exhibit up to 10-fold greater clearance of B. burgdorferi from target tissues compared with wild-type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. To further delineate these IL-10-mediated immune effects, kinetic studies indicated that spirochete dissemination to target tissues is similar in both wild-type and IL-10−/− mouse strains, and that enhanced clearance of B. burgdorferi in IL-10−/− mice is correlated with increased B. burgdorferi-specific Ab as early as 2 wk postinfection. Immunoblot analysis indicated that Abs produced by infected IL-10−/− and wild-type mice recognize similar ranges of spirochetal Ags. Immune sera from IL-10−/− and wild-type mice also exhibited similar bactericidal activity in vitro, and passive transfer of these immune sera into B. burgdorferi-infected SCID mice caused similar reductions of bacterial numbers in target tissues. Infectious dose studies indicated that 8-fold more B. burgdorferi were needed to efficiently infect naive IL-10−/− mice, suggesting these animals possess higher innate barriers to infection. Moreover, macrophages derived from IL-10−/− mice exhibit enhanced proinflammatory responses to B. burgdorferi stimulation compared with wild-type controls, and these responses are not significantly affected by the presence of immune serum. These findings confirm that B. burgdorferi clearance by innate immune responses is more efficient in the absence of IL-10, and these activities are not directly related to increased levels of B. burgdorferi-specific Ab.

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

“…A deficiency in IL-10 has been linked to reduced microbial loads and increased levels of B. burgdorferi-specific antibodies (3,50); however, these findings were observed at least 2 weeks after infection. In addition, a robust innate immune response, rather than the borreliacidal antibody response, was implicated in the reduced levels of B. burgdorferi in the tissues of IL-10-deficient mice (50). Therefore, the lack of significant borreliacidal antibody activity in our IL-10-deficient mice may not be surprising.…”

“…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.…”

BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

“…In the mice infected with the high dose, on day 4 for SH200/pBBE22luc and day 7 for ML23/pBBE22luc, a high level of fluorescence is observed on the abdomens of the mice radiating from the site of B. burgdorferi injection. On day 10 for both strains, the luminescence is decreased because of partial clearing of spirochetes by virtue of the burgeoning humoral response to B. burgdorferi (13,61,64). On day 14, the signal returns but is now distributed more widely across the entire torso and extends to the limbs and head.…”

CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis

“…IL-10 is an anti-inflammatory cytokine, induced by Bb lipoproteins, that negatively regulates the immune response against Bb by inhibiting the production of proinflammatory cytokines by macrophages (28). IL-10 Ϫ/Ϫ mice on an arthritis-resistant B6 background showed increased acute arthritis upon Bb infection (8) (29). In our system, the acute inflammatory response was not affected, because no differences in the ankle width were observed between the CD28 Ϫ/Ϫ and the control group during the early phase of the disease.…”