Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis.

Junpei Kimura,Osamu Ichii,Kosuke Miyazono,Taro Horino,Yasuhiro Kon,Teppei Nakamura,Saori Otsuka-Kanazawa

doi:10.1038/srep07290

Junpei Kimura, Osamu Ichii + Show 5 more

Open Access

https://doi.org/10.1038/srep07290

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Abstract

Members of the Toll-like receptor (TLR) family serve as pathogen sensors and participate in local autoimmune responses. This study found a correlation between glomerular injury and TLR expression by analysing BXSB/MpJ-Yaa (BXSB-Yaa) lupus model mice. In isolated glomeruli, the mRNA expression of several TLRs was higher in BXSB-Yaa mice than in healthy control BXSB mice. In particular, the expression of Tlr8 and its downstream cytokines was markedly increased. In mouse kidneys, TLR8 protein and mRNA localized to podocytes, and TLR8 protein expression in the glomerulus was higher in BXSB-Yaa mice than in BXSB mice. In BXSB-Yaa mice, the glomerular levels of Tlr8 mRNA negatively correlated with the glomerular levels of podocyte functional markers (Nphs1, Nphs2, and Synpo) and positively correlated with urinary albumin levels. Furthermore, the glomerular and serum levels of miR-21, a putative microRNA ligand of TLR8, were higher in BXSB-Yaa mice than in BXSB mice. The urinary levels of Tlr8 mRNA were also higher in BXSB-Yaa mice than in BXSB mice. In conclusion, the overexpression of TLR8 correlates with the progression of podocyte injury in glomerulonephritis. Thus, altered levels of urinary Tlr8 mRNA might reflect podocyte injury.

Highlights

Members of the Toll-like receptor (TLR) family serve as pathogen sensors and participate in local autoimmune responses
Urinary albumin-to-creatinine ratio levels, which serve as an index of glomerular dysfunction, were higher in BXSB-Y-linked autoimmune acceleration (Yaa) mice than in BXSB mice at 4 months of age (Table 1)
According to Fu et al, anti-glomerular basement membrane (GBM) antibody-treated mice develop mild GN, but when the treatment is coupled with specific TLR ligands, including peptidoglycan (TLR2), poly (I:C) (TLR3), LPS (TLR4), or flagellin (TLR5), the treated mice developed GN of greater severity associated with the activation of the NF-kB pathway[23]

Summary

Introduction

Members of the Toll-like receptor (TLR) family serve as pathogen sensors and participate in local autoimmune responses. This study found a correlation between glomerular injury and TLR expression by analysing BXSB/MpJ-Yaa (BXSB-Yaa) lupus model mice. TLR8 protein and mRNA localized to podocytes, and TLR8 protein expression in the glomerulus was higher in BXSB-Yaa mice than in BXSB mice. NZB, (NZB 3 NZW) F1 hybrid, BXSB/MpJ-Yaa (BXSB-Yaa), and MRL/MpJ-lpr mice are commonly used as spontaneous SLE models[3] These strains develop systemic autoimmune diseases characterized by increased serum autoantibody levels and vasculitis, in addition to GN that is similar to human LN3. TLRs are expressed on the plasma membrane or intracellular vesicular membrane of hematopoietic and nonhematopoietic cells[8] They have been characterized as innate immune sensors that recognize danger signals arising from pathogen-associated molecular patterns (PAMPs), including flagellin, lipopolysaccharide (LPS), and nucleic acids derived from bacteria, mycobacteria, mycoplasma, fungi, and viruses[8]. Values are the mean 6 s.e. dsDNA, double-strand DNA antibody; sBUN, serum blood urea nitrogen; sCre, serum creatinine; uACR, urinary albumin-to-creatinine ratio. *Significantly different from BXSB mice at the same age (Mann-Whitney U-test, P , 0.05); n $ 3

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