Autoimmune rheumatologic diseases

Oral

The Effect of Functional Human tlr8 on Autoimmunity and Renal Inflammation in Systemic Lupus Erythematosus

Friday, June 16
6:15 PM - 7:30 PM

Objective: Lupus nephritis (LN) causes significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). Using a systems biology approach we found that renal macrophage functional pathways, linking phagocytosis with activation of TLR pathways, are shared between mice and humans with LN. Surprisingly, we observed overexpression of TLR8, but not other endosomal TLRs, in resident renal macrophages from nephritic mice as well as in human LN kidneys. Our goal was to evaluate the effect of functional human TLR8 (huTLR8) on autoimmunity and renal inflammation.


Methods: Because mouse TLR8 does not recognize ssRNA, NZW/B6.Yaa mice expressing huTLR8 as a BAC transgene (huTR8tg) were generated and followed clinically. huTLR8 mRNA was confirmed by qPCR. 24-week-old male mice were administered TL-506 (TLR8-agonist) subcutaneously for 4weeks and spleens and kidneys were harvested for analysis after 8weeks. Mitochondrial respiration of TLR8-stimulated bone marrow-derived macrophages (BMDMs) was assessed using the Seahorse XF Analyzer.


Results: A single copy of huTLR8 in NZW/B6.Yaa mice did not exacerbate/accelerate disease however TLR8-agonist administration appeared to enhance germinal center formation and plasma cell generation in male huTLR8tg mice. TL-506-stimulated BMDMs from huTLR8tg mice had a significant decrease in mitochondrial respiration and increased glycolysis compared to wt BMDMs.


Conclusions: One copy of huTLR8 does not initiate/exacerbate lupus in NZW/B6.Yaa mice. We are now following lupus mice with 2 copies of huTLR8 to determine effects on lupus phenotype. Further elucidating how TLR8 influences macrophage metabolism and phenotype will improve our understanding of the role of this TLR in inflammation and autoimmunity.

Naomi I. Maria

PostDoc
The Feinstein Institute for Medical Research

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    Megan Woods

    The Feinstein institute for Medical Research

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      Shani Martinez

      The Feinstein institute for Medical Research

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        Weiqing Huang

        The Feinstein institute for Medical Research

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          Anne Davidson

          The Feinstein institute for Medical Research

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