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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<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>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<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>-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.<\/jats:p>","DOI":"10.1128\/iai.00781-17","type":"journal-article","created":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T12:01:49Z","timestamp":1515412909000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["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"],"prefix":"10.1128","volume":"86","author":[{"given":"Bikash","family":"Sahay","sequence":"first","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA"},{"name":"Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Gainesville, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Bashant","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole L. 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