Background and aims Lupus nephritis (LN) is a significant cause of morbidity and mortality. In recent systems biology work we found that renal macrophage functional pathways that link phagocytosis with activation of TLR pathways and disposal of excess cellular components are shared between mice and humans with lupus nephritis. Surprisingly we found that in two different lupus strains there is marked upregulation of renal TLR8 expression restricted to resident renal macrophages.
Methods Because mouse TLR8 does not recognise ssRNA, we generated NZW/B6.Yaa mice expressing a functional form of human TLR8 as a BAC transgene to examine the effect of human TLR8 on systemic immunity and renal inflammation. TLR8 mRNA was quantitated by qPCR. Male and female mice were followed clinically for up to one year and harvested for flow cytometry analysis of spleens and kidneys. 24-week-old male mice were administered TL-506 subcutaneously for 4 weeks and harvested after 8 weeks.
Results A single dose of human TLR8 in NZW/B6.Yaa mice did not exacerbate disease or accelerate disease or change the immune phenotype of the spleens or kidneys. However administration of a TLR8 agonist to male NZW/B6.Yaa mice appeared to enhance germinal centre formation and plasma cell generation in transgenic mice.
Conclusions A single dose of human TLR8 is not sufficient to initiate or exacerbate lupus in NZW/B6.Yaa mice. Preliminary findings suggest that the mice may be hyperresponsive to a TLR8 agonist. Lupus mice with 2 copies of the human TLR8 transgene have been generated to determine whether an extra dose will affect lupus onset or phenotype.
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