Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity

Abstract

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusb h . C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusb h allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs

Borrelia burgdorferi Arthritis–Associated Locus Bbaa1 Regulates Lyme Arthritis and K/B×N Serum Transfer Arthritis through Intrinsic Control of Type I IFN Production

“…QTL analysis for Lyme disease severity that recently allowed identification of Gusb as a major regulator of Lyme arthritis also revealed a similar regulatory potential for the K/B×N serum transfer model of RA (33). This prompted us to consider the possibility that Bbaa1 might also regulate RA.…”

“…Gusb was positionally cloned as a major regulator of Lyme arthritis severity within Bbaa2 on Chr5, and the disease exacerbating Gusb allele was also found to increase the severity of the K/B×N model of RA (33). The identification of Gusb provided an unexpected correlation of disease severity with reduced lysosomal enzyme activity and the subsequent accumulation of undigested glycosaminoglycans in joint tissue of both B. burgdorferi infected and autoantibody treated arthritis.…”

“…), as described(38). K/B×N serum (100μl) was administered by intraperitoneal injection on days 0 and 2 (33, 39). Rear ankle measurements were made prior to serum transfer on Day 0, and on Days 1, 2, 4, and 7.…”

“…This approach led to the identification of 23 B. burgdorferi associated loci ( Bbaa ) regulating responses to B. burgdorferi infection, and included six Bbaa regulating arthritis severity (30–32). We have recently validated the utility of this rigorous and unbiased approach with the positional cloning of beta-glucuronidase, Gusb, within Bbaa2 on Chr5, as a major determinant of Lyme arthritis severity in mice (33). Gusb also regulates the severity of rheumatoid arthritis (RA) in mice.…”

Synthesis of benzimidazole derivatives as potent β-glucuronidase inhibitors

“…Increased activity of b-glucuronidase has resulted in various health issues that includes renal disorders [4], urinary tract infections [5,6], epilepsy [7,8], renal transplant rejection [9,10], neoplasm of bladder [11] and breast cancers [12]. Further, the enzyme has been found to be released into fluid in the cavities of synovial joints [13] and is involved in the disorders like those of rheumatoid arthritis [14]. Excessive expression of b-glucuronidase is also reported in some hepatic related disorders [15,16].…”