Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling

Infect Immun. 2018 Mar 22;86(4):e00781-17. doi: 10.1128/IAI.00781-17. Print 2018 Apr.


Host genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacterium Borrelia burgdorferi C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated with B. burgdorferi produce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences of B. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

Keywords: Borrelia; IL-10; Lyme; macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / etiology
  • Arthritis / metabolism
  • Arthritis / pathology
  • Borrelia burgdorferi / physiology*
  • Chromatin Assembly and Disassembly* / genetics
  • Cyclic AMP / metabolism*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression Profiling
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lipopolysaccharide Receptors / metabolism
  • Lyme Disease / genetics
  • Lyme Disease / immunology
  • Lyme Disease / metabolism*
  • Lyme Disease / microbiology*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Monocytes / immunology
  • Monocytes / metabolism
  • Monocytes / microbiology
  • Promoter Regions, Genetic
  • STAT3 Transcription Factor / metabolism
  • Sp1 Transcription Factor / metabolism
  • Transcriptional Activation
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Cytokines
  • Lipopolysaccharide Receptors
  • STAT3 Transcription Factor
  • Sp1 Transcription Factor
  • Interleukin-10
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases