Genetic Control of Lyme Arthritis by <i>Borrelia burgdorferi</i> Arthritis–Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin

Abstract

Previously, using a forward genetic approach, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus underlying <i>Borrelia burgdorferi</i> arthritis-associated locus 1 (<i>Bbaa1</i>). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3-<i>Bbaa1</i> mice. Genetic control of IFN-β expression was also identified in bone marrow-derived macrophages stimulated with <i>B. burgdorferi</i>, and it was responsible for feed-forward amplification of IFN-stimulated genes. Reciprocal radiation chimeras between B6.C3-<i>Bbaa1</i> and C57BL/6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the <i>Bbaa1</i> interval, and confirmed the contribution of type I IFN genes to Lyme arthritis. RNA sequencing of resident CD45^- joint cells from advanced interval-specific recombinant congenic lines identified myostatin as uniquely upregulated in association with <i>Bbaa1</i> arthritis development, and myostatin expression was linked to IFN-β production. Inhibition of myostatin in vivo suppressed Lyme arthritis in the reduced interval <i>Bbaa1</i> congenic mice, formally implicating myostatin as a novel downstream mediator of the joint-specific inflammatory response to <i>B. burgdorferi</i>.