Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus

Abstract

The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.

Keywords: mouse models; systemic lupus erythematosus; toll-like receptor.

Figure 1

TLR signaling and expression in immune cells. TLRs are a class of proteins that are involved in immune responses upon recognizing molecules such as pathogen-associated molecular patterns (PAMPs), lipopolysaccharide (LPS), profilin, flagellin, ssDNA, dsDNA, ssRNA, and dsRNA. TLR1-TLR13 is found in mice, and TLR1-TLR10 is found in humans. The signaling pathways downstream of TLR activation are complex but can be roughly divided into MyD88-dependent and TIR domain-containing adapter-inducing IFN-β (TRIF)-dependent pathways. The myeloid differentiation factor 88 (MyD88)-dependent pathway is utilized by all TLRs except TLR3, while TLR4 can activate both pathways. Nuclear factor-kB (NFkB) comprises a family of transcription factors regulating genes involved in immune and inflammatory responses. Interferon regulatory factors (IRFs) regulate the transcription of interferons (IFNs), primarily type I IFNs. In the figure, the size of the TLR7-TLR9 letters in the different immune cells indicate their expression levels in these cells. Created with BioRender.com. DC, dendritic cell; pDC, plasmacytoid dendritic cell; NK, natural killer cell; ss, single-stranded; ds, double-stranded; IFN, interferon.

Figure 2

Overview of single-gene knockout (KO), knock-in (KI), or mutations in mice causing a lupus-like phenotype by influencing toll-like receptor (TLR) signaling and gene expression. Normal signaling pathways are shown with single-gene KO or mutations marked in red. Tlr7 duplications in both spontaneous lupus models carrying the Yaa gene and in TLR7 transgenic mice induce spontaneous autoimmunity. Dnase1l3 and Dnase1 KO mice have reduced clearance of circulating chromatin, thus increasing the antigens for TLRs. PLD4 mutant mice have increased signaling through TLRs due to reduced degradation of ssDNA in endosomes. CRIF1 deficiency influences CDK2-induced DNA repair, NRF2 binding, and formation of the ETC complex [50]. BLIMP1 normally controls the binding of IRF1, 2, and 4 and increases IL-10 expression. It also suppresses the expression of IRAK3 an inhibitor of IRF7 signaling [51]. PTPN22 inhibits various signaling pathways but acts as a selective promoter of type I interferon by promoting autoubiquitination of TRAF3 and phosphorylation of IRF3 and IRF7 [23]. LYN phosphorylates ITAM and PLCγ2 and inhibits IRF5 activation [52]. PLCγ2 activation via tyrosine kinases like LYN leads to increased Ca²⁺ signaling and a gain-of-function mutation, which was shown to cause hyperreactive external calcium entry [53]. WASP affects many parts of the BCR signaling pathways [54] and B-cell-specific WAS deficient mice develop autoantibodies against both DNA and RNA [48]. IRE1α is an ER membrane protein important for transducing signals of misfolded protein accumulation in ER to the nucleus by splicing X-box binding 1 (XBP1) mRNA and leading to the production of stable transcription factor XBP1 (XBP1s) [55]. XBP1s targets various genes involved in multiple cellular functions [56]. Created with BioRender.com. KI, knock-in; KO, knockout; PLD4, phospholipase D family member 4; UPR, unfolded protein response; ssDNA, single-stranded DNA; ETC, electron transport chain; BCR, B-cell receptor; WAS, Wiskott–Aldrich syndrome; ER, endoplasmatic reticulum; IRF, interferon regulatory factors; CRIF, CR6-interacting factor 1; IRAK, interleukin-1 receptor-associated kinase; PTPN, protein tyrosine phosphatase nonreceptor 22; XBP1, X-box binding 1; PLCγ2, phospholipase Cγ2; BLIMP, B-lymphocyte-induced maturation protein.

Figure 3

TLR-driven autoantibody production. Recognition of extracellular nucleic acids or proteins bound to nucleic acids by naïve B cells via the B-cell receptor (BCR) causes internalization of the BCR–antigen complex, which ends up in an endosome. Endosomal toll-like receptors (TLRs) like TLR7 and TLR9 may then also encounter the internalized nucleic acid-containing antigens. Co-engagement of BCR and TLR via antigens can lead to activation of the B cell and induce isotype switching to IgG. Consequently, a large number of autoantibody secreting plasma cells can be generated. Created with BioRender.com. RBP, RNA-binding protein.