Toll-like receptors in lupus nephritis

Abstract

The pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) is based on the loss of self-tolerance against ubiquitous autoantigens involving all mechanisms of adaptive immunity. However, data accumulating over the last decade imply an important role also for numerous elements of innate immunity, namely the Toll-like receptors in the pathogenesis of SLE. Here we discuss their role in the most common organ complication of SLE, i.e. lupus nephritis. We summarize experimental and clinical data on the expression and functional contribution of the Toll-like receptors in immune complex glomerulonephritis, and intrarenal inflammation. Based on these discoveries Toll-like receptors are evolving as therapeutic targets for the treatment of SLE and lupus nephritis.

Keywords: Glomerulonephritis; Immune complex; Inflammasome; Innate immunity; Interferon.

Fig. 1

Toll-like receptor (TLR) signalling pathways. TLR1, TLR2, TLR4, TLR5, TLR6, TLR11, TLR12 as homo or heterodimers bind to their respective ligands at the cell surface, whereas TLR3, TLR7/TLR8, TLR9, and TLR13 sense nucleic acids in endosomes. TLR4 localizes at both the plasma membrane and the endosomes. The Toll–IL-1-resistence (TIR) domains of TLRs-dimers bind TIR domain-containing adaptor proteins (either myeloid differentiation primary-response protein 88 (MYD88), or TIR domain-containing adaptor protein inducing IFNβ (TRIF) and TRIF-related adaptor molecule (TRAM)). Downstream signalling pathways of TLRs involve IL-1R-associated kinases (IRAKs), IκB kinase -alpha, beta, gamma and epsilon (IKK αβγε-) and the adaptor molecules TNF receptor-associated factors (TRAFs). These protein complexes activate p50 and p65, as well as various transcription factors such as interferon-regulatory factors (IRFs) and activator protein 1 (AP1). TLR signalling leads to the induction of pro-inflammatory cytokines or the induction of type I interferon (IFN)