Autoimmune rheumatologic diseases
Systemic sclerosis (SSc) is a complex, heterogeneous autoimmune disease characterized by vascular abnormalities, immune involvement, and extensive fibrosis of the skin and internal organs. Myeloid dendritic cells (mDCs) are shown to be dysregulated in SSc and are implicated in the pathogenesis. To further explore the role of mDCs in SSc, we performed a transcriptomic profiling of circulating mDCs from SSc patients and healthy donors, and built a gene co-expression network to identify genes potentially involved in disease pathogenesis.
Within the co-expression network we identified gene clusters (modules) that significantly correlated with SSc and/or associated clinical traits. By applying enrichment analysis we observed that one module mainly consisted out of immune-regulatory genes down-regulated in the most fibrotic SSc patients. Using network parameters and literature-driven regulatory network analysis, the orphan nuclear receptor 4A subfamily (NR4A1, NR4A2, NR4A3) were identified as the key regulators of this module. The role and functionality of NR4As has not been studied hitherto in mDCs and in SSc, but they have recently emerged as important regulators of inflammation and fibrosis in other cell types. The down-regulation of NR4A1/2/3 was validated in an independent SSc cohort.
To further elicit the regulatory potential of NR4As in mDCs and their implication in SSc, we are currently performing siRNA knowdown assays, functional assays and ChIP-sequencing. Thus, by applying both bioinformatic and experimental approaches, we are exploring the functional role of the NR4A orphan receptor subfamily and establishing them as key players in SSc pathogenesis.