Issue No. 34, November 2020
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
Scavenger receptor-A is a biomarker and effector of Rheumatoid Arthritis: A large-scale multicenter study
 
Dr. Xiang-Yang Wang and collaborators have demonstrated that soluble scavenger receptor A (sSRA) is a potential biomarker in diagnosis of rheumatoid arthritis (RA), and that targeting SR-A may be a novel therapeutic strategy.
 
  • The levels of sSRA in RA patients are substantially higher than those of patients with other rheumatic diseases or healthy controls. Combining sSRA with currently established biomarkers may help improve the accuracy and sensitivity of RA diagnosis in the clinic.

  • Using mouse arthritis models, the investigators demonstrate that administration of SRA accelerates the onset of experimental arthritis in mice, whereas inhibition of SRA ameliorates disease pathogenesis.

  • These findings may lead to novel diagnostic and treatment strategies for clinical management of RA.
 
RA is a chronic autoimmune disease that can lead to joint destruction, disability, and premature mortality. It affects about 1% of the population worldwide. Although early diagnosis of RA is often associated with a better response to treatment, reduced co-morbidity, and lower mortality, the rate of disease remission is only 8.6%. However, current diagnostic tools are not sufficiently accurate or sensitive in the early stages of RA. New research from Dr. Xiang-Yang Wang and colleagues demonstrated that soluble form of SRA in the circulation can be used as a potential RA diagnostic marker for complementary diagnosis of early RA as well as seronegative RA.

SRA, also termed CD204, is an innate pattern recognition receptor primarily expressed on cells of myeloid origin, which displays pleiotropic biological functions. While there is a wealth of literature describing the roles of SRA in lipid metabolism, cardiovascular diseases, and pathogen recognition, its potential role in autoimmune disorders such as RA had not been examined. In the present study, the levels of sSRA in patients with RA or other types of rheumatic diseases was assessed. The serum levels of sSRA in patients with RA were shown to be significantly higher than those of healthy individuals or patients with other common rheumatic diseases (Figure 1), suggesting selective elevation of sSRA in RA patients.
The involvement of SRA in arthritis development was validated using mice with ablation of the SRA gene. There was an evident increase of serum sSRA in wild type (WT) mice following collagen-induced arthritis (CIA), which positively correlated with clinical scores of arthritis during disease progression (Figure 2A). Strikingly, genetic ablation of SRA was found to render mice fully protected from CIA (Figure 2B). Absence of SRA also reduced arthritis-associated cartilage erosion and inflammatory exudation in the articular cavity (Figure 2C).
Figure 1. The prevalence of soluble SRA (sSRA) in RA patients. The serum levels of sSRA were significantly higher in patients with RA than those of healthy individuals and those with other common rheumatic diseases and non-autoimmune inflammatory diseases: Sjogren’s Syndrome (SS), systemic lupus erythematosus (SLE), osteoarthritis (OA) and healthy controls.
Figure 2. Reduced incidence of autoimmune arthritis and decreased inflammation in SRA deficient mice. (A) The serum levels of mouse sSRA in naïve C57BL/6 mice or arthritic mice with different clinical scores were examined by ELISA (n=3). (B) Male WT (n=5) and SRA-/- (n=5) mice were subjected to collagen-induced arthritis (CIA). The disease severity was monitored. (C) Representative gross image of arthritic symptoms was recorded at six weeks post CIA induction. Inflammatory cell infiltration and bone erosion were evaluated by H&E staining. Red star indicates inflammatory cell infiltration. Arrow indicates bone erosion. (D) Serum level of IL-17A in the arthritic mice (n=3) was assessed by ELISA. (E) Splenocytes from naïve control or CIA mice were cultured in the presence of denatured collagen, followed by analysis of IL-17A levels in the medium (left). The frequencies of IL-17A-producing cells were also determined by ELISPOT (right). 
Additionally, loss of SRA impaired the pathogenic T-helper cell 17 (Th17) response in arthritic mice, indicated by reduced IL-17A cytokine in the blood (Figure 2D), diminished production of IL-17A by splenocytes upon collagen stimulation (Figure 2E), supporting SRA as a key factor in driving inflammatory and pathogenic processes in arthritis. Together, these results indicate that use of sSRA for RA early diagnosis could benefit patients by allowing their earlier access to treatment, thereby preserving joint function and minimizing economic cost. Given a potential role of SRA in RA pathogenesis, supported by findings in mouse models of RA, therapeutic approaches targeting human SRA could be a promising approach for disease intervention.

Dr. Chunqing Guo, Assistant Professor in the Department of Human and Molecular Genetics (HMG) at Virginia Commonwealth University, School of Medicine is one of the lead authors of this paper, and performed much of the biological and animal work. The present study was supported in part by Virginia Commonwealth University Research Development Funds and US Department of Defense Award (W81XWH1910538 to X.-Y.W.). VCU Flow cytometry facility was supported in part by NCI Cancer Center Support Grant to VCU Massey Cancer Center P30CA16059.

Publications:
 
F. Hu, X. Jiang, C. Guo, Y. Li, S. Chen, W. Zhang, Y. Du, P. Wang, X. Zheng, X. Fang, X. Li, J. Song, Y. Xie, F. Huang, J. Xue, M. Bai, Y. Jia, X. Liu, L. Ren, X. Zhang, J. Guo, H. Pan, Y. Su, H. Yi, H. Ye, D. Zuo, J. Li, H. Wu, Y. Wang, R. Li, L. Liu, X.Y. Wang, Z. Li, Scavenger receptor-A is a biomarker and effector of rheumatoid arthritis: A large-scale multicenter study. Nat Commun. 2020 Apr 20;11(1):1911. PMCID: PMC7171100
 
About the Investigators: Xiang-Yang Wang, PhD, is Harry and Judy Wason Distinguished Professor in the Department of HMG; Associate Scientific Director of Immunology, VCU Institute of Molecular Medicine; and co-leader of Developmental Therapeutics Program, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA. Chunqing Guo, PhD, is an Assistant Professor in the Department of HMG and contributes to this research study as co-first author.