Cylindromatosis (CYLD), a Deubiquitinase, Attenuates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

What is it about?

factor-κB in various cells. However, its potential roles in glomerular inflammation remain unclear. Because the activation of the Toll-like receptor 3 (TLR3)/type I interferon (IFN) pathways plays a pivotal role in chronic kidney diseases (CKD), we examined the role of CYLD in the TLR3 signaling in cultured human mesangial cells (MCs). Methods: We stimulated CYLD-silenced MCs with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of dsRNA, and studied representative TLR3/IFN-β pathways (i.e., TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/ CCL5, and TLR3/IFN-β/melanoma differentiation associated gene 5 (MDA5)/CXCL10 axes) using RT-PCR, western blotting, and ELISA. We also used immunofluorescence staining and microscopy to examine mesangial CYLD expression in biopsied specimens from patients with CKD. Results: CYLD silencing resulted in an increase of poly IC-induced RIG-I and MDA5 protein levels and increased CCL5 and CXCL10 mRNA and protein expression, but unexpectedly decreased mRNA expressions of RIG-I and MDA5. Interestingly, CYLD silencing did not affect IFN-β or the phosphorylated STAT1 (signal transducers and activator of transcription protein 1). CYLD was highly expressed in biopsied specimens from patients with proliferative lupus nephritis (LN). Conclusion: CYLD inhibits post-transcriptional regulation of RIG-I and MDA5 expression following TLR3 activation in MCs. CYLD may be involved in the pathogenesis of CKD, especially pathogenesis of LN.

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Why is it important?

Because immune and inflammatory reactions downstream of TLR3 signaling are important in host defenses against viral or “pseudoviral” infections in CKD, especially in LN, we believe that regional CYLD dysregulation in MCs may lead to inflammatory renal diseases. Thus, CYLD is, at least in part, involved in the pathogenesis of CKD, but this theory remains speculative. Since we found that cross-talk between functional molecules induced by TLR3 activation, such as type I IFN-stimulated genes and pro-inflammatory chemokines/ cytokines stimulated by type I IFNs, plays protective or deleterious roles during the pathogenesis of glomerular inflammation in MCs in CKD, detailed understanding of interactions among these molecules during immune reactions may lead to the development of new therapeutic strategies for CKD.

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