Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis

Abstract

MicroRNA-155 has been shown to play a role in immune activation and inflammation, and is suppressed by IL-10, an important anti-inflammatory cytokine. The established involvement of IL-10 in the murine model of Borrelia burgdorferi-induced Lyme arthritis and carditis allowed us to assess the interplay between IL-10 and miR-155 in vivo. As reported previously, Mir155 was highly upregulated in joints from infected severely arthritic B6 Il10-/- mice, but not in mildly arthritic B6 mice. In infected hearts, Mir155 was upregulated in both strains, suggesting a role of miR-155 in Lyme carditis. Using B. burgdorferi-infected B6, Mir155-/-, Il10-/-, and Mir155-/- Il10-/- double-knockout (DKO) mice, we found that anti-inflammatory IL-10 and pro-inflammatory miR-155 have opposite and somewhat compensatory effects on myeloid cell activity, cytokine production, and antibody response. Both IL-10 and miR-155 were required for suppression of Lyme carditis. Infected Mir155-/- mice developed moderate/severe carditis, had higher B. burgdorferi numbers, and had reduced Th1 cytokine expression in hearts. In contrast, while Il10-/- and DKO mice also developed severe carditis, hearts had reduced bacterial numbers and elevated Th1 and innate cytokine expression. Surprisingly, miR-155 had little effect on Lyme arthritis. These results show that antagonistic interplay between IL-10 and miR-155 is required to balance host defense and immune activation in vivo, and this balance is particularly important for suppression of Lyme carditis. These results also highlight tissue-specific differences in Lyme arthritis and carditis pathogenesis, and reveal the importance of IL-10-mediated regulation of miR-155 in maintaining healthy immunity.

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

“…This is consistent with the role of miRNAs in RA . Intriguingly, mice lacking either miR‐146a or miR‐155 were shown to develop more severe Lyme arthritis or carditis …”

“…194 Intriguingly, mice lacking either miR-146a or miR-155 were shown to develop more severe Lyme arthritis or carditis. 195,196 Recently, in groups of patients with different stages of Lyme arthritis, alternate miRNA profiles were observed. Elevated levels of miR-223 and low levels of miRNAs such as miR-146a, miR-155, and miR-142 were found in synovial fluid of Lyme arthritis patients prior to antibiotic therapy (n = 5).…”

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

“…However, excessively high IFN responses early in infection may also lead to adverse disease outcomes (Strle, Jones, Drouin, Li, & Steere, ). These findings indicate that the magnitude of Type I and/or Type II IFN responses must be sufficient to mount an appropriate antibacterial immune response but must also be tightly regulated to avoid excess inflammation‐induced tissue pathologies (Lochhead et al, ).…”

Spirochetal Lipoproteins and Immune Evasion

“…As a bodily response to the vast amounts of pro-inflammatory cytokines produced upon spirochetal lipoprotein presence, monocytes have also been seen to produce IL-10 upon being presented with B. burgdorferi lipoproteins (71–75). IL-10, unlike cytokines such as IL-1 and IL-12, is known to reduce inflammation via TLR-pathway downregulation and can therefore assist in combatting the spirochetal infection as well as any possible chronic effects such as arthritis (76, 77). The above was confirmed in recent mice studies that utilized a TLR2 agonist, Pam3CSK4, to induce IL-10 production which attenuated inflammatory response to Leptospira (78).…”