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Forward genetics using C3H mice with severe Lyme arthritis and C57BL\/6 (B6) mice with mild Lyme arthritis identified the<jats:italic>Borrelia burgdorferi arthritis-associated locus 1<\/jats:italic>(<jats:italic>Bbaa1<\/jats:italic>) on chromosome 4 (Chr4) as a regulator of<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>-induced IFN\u03b2 expression and Lyme arthritis severity. B6 mice introgressed with the C3H allele for<jats:italic>Bbaa1<\/jats:italic>(B6.C3-<jats:italic>Bbaa1<\/jats:italic>mice) displayed increased severity of arthritis, which is initiated by myeloid lineage cells in joints. Using advanced congenic lines, the physical size of the<jats:italic>Bbaa1<\/jats:italic>interval has been reduced to 2 Mbp, allowing for identification of potential genetic regulators. Small interfering RNA (siRNA)-mediated silencing identified<jats:italic>Cdkn2a<\/jats:italic>as the gene responsible for<jats:italic>Bbaa1<\/jats:italic>allele-regulated induction of IFN\u03b2 and IFN-stimulated genes (ISGs) in bone marrow-derived macrophages (BMDMs). The<jats:italic>Cdkn2a<\/jats:italic>-encoded p19 alternative reading frame (p19ARF) protein regulates IFN\u03b2 induction in BMDMs as shown by siRNA silencing and overexpression of ARF.<jats:italic>In vivo<\/jats:italic>studies demonstrated that p19ARF contributes to joint-specific induction of IFN\u03b2 and arthritis severity in<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>-infected mice. p19ARF regulates<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>-induced IFN\u03b2 in BMDMs by stabilizing the tumor suppressor p53 and sequestering the transcriptional repressor BCL6. Our findings link p19ARF regulation of p53 and BCL6 to the severity of IFN\u03b2-induced Lyme arthritis<jats:italic>in vivo<\/jats:italic>and indicate potential novel roles for p19ARF, p53, and BCL6 in Lyme disease and other IFN hyperproduction syndromes.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010365","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T21:25:52Z","timestamp":1648157152000},"page":"e1010365","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFN\u03b2-mediated Lyme arthritis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9108-6927","authenticated-orcid":true,"given":"Jinze","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie K.","family":"Paquette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda C.","family":"Richards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Mulvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F.","family":"Zachary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-8843","authenticated-orcid":true,"given":"Cory","family":"Teuscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7214-5987","authenticated-orcid":true,"given":"Janis J.","family":"Weis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"issue":"5","key":"ppat.1010365.ref001","doi-asserted-by":"crossref","first-page":"725","DOI":"10.7326\/0003-4819-107-5-725","article-title":"The clinical evolution of Lyme arthritis","volume":"107","author":"AC Steere","year":"1987","journal-title":"Ann Intern 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