1. The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFNβ-mediated Lyme arthritis.
- Author
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Li, Jinze, Ma, Ying, Paquette, Jackie K., Richards, Amanda C., Mulvey, Matthew A., Zachary, James F., Teuscher, Cory, and Weis, Janis J.
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LYME disease , *TYPE I interferons , *SMALL interfering RNA , *BORRELIA burgdorferi , *MYELOID cells - Abstract
Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity. B6 mice introgressed with the C3H allele for Bbaa1 (B6.C3-Bbaa1 mice) displayed increased severity of arthritis, which is initiated by myeloid lineage cells in joints. Using advanced congenic lines, the physical size of the Bbaa1 interval has been reduced to 2 Mbp, allowing for identification of potential genetic regulators. Small interfering RNA (siRNA)-mediated silencing identified Cdkn2a as the gene responsible for Bbaa1 allele-regulated induction of IFNβ and IFN-stimulated genes (ISGs) in bone marrow-derived macrophages (BMDMs). The Cdkn2a-encoded p19 alternative reading frame (p19ARF) protein regulates IFNβ induction in BMDMs as shown by siRNA silencing and overexpression of ARF. In vivo studies demonstrated that p19ARF contributes to joint-specific induction of IFNβ and arthritis severity in B. burgdorferi-infected mice. p19ARF regulates B. burgdorferi-induced IFNβ 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 IFNβ-induced Lyme arthritis in vivo and indicate potential novel roles for p19ARF, p53, and BCL6 in Lyme disease and other IFN hyperproduction syndromes. Author summary: Lyme disease is caused by infection with the tick-transmitted bacterium Borrelia burgdorferi. Although different isolates of B. burgdorferi have distinct potential for dissemination and tissue invasion, factors intrinsic to the infected host also play an important role in directing the severity of Lyme disease. In the animal model, infected C3H mice develop severe Lyme arthritis following elevation of type I IFN in joint tissue, while in C57BL/6 (B6) mice arthritis is mild and not associated with type I IFN. We demonstrated that the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) intrinsically controls the magnitude of IFNβ production and the severity of Lyme arthritis in C3H vs B6 mice. The Cdkn2a gene was positionally identified as the regulator of IFNβ within Bbaa1, and determined to function through its protein product p19 alternative reading frame (p19ARF). ARF regulates IFNβ expression and Lyme arthritis severity by modulating the activities of the tumor suppressor p53 and transcriptional repressor BCL6. Our study provides new insight and potential therapeutic targets for the investigation of type I IFN-dependent Lyme arthritis and other IFN-driven diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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