Tlr5deficiency exacerbates lupus-like disease in the MRL/lprmouse model

Abstract A leaky gut has been linked to numerous autoimmune disorders, including systemic lupus erythematosus (SLE). We had previously reported significant upregulation of anti-flagellin antibodies in the blood of SLE patients and lupus-prone MRL/lpr mice, which led to our hypothesis that a leaky gut drove SLE through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5). Here, we investigated the initiation and progression of lupus-like disease in MRL/lpr mice with global Tlr5 deletion generated by CRISPR-Cas9. Contrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus-like disease with Tlr5 deficiency in MRL/lpr mice. A significantly higher level of proteinuria was observed in Tlr5 −/−female MRL/lpr mice compared to Tlr5 +/−and Tlr5 +/+female littermates, suggesting aggravated glomerulonephritis with Tlr5 deficiency. In the kidney, the deletion of Tlr5 significantly increased renal infiltration of activated conventional and monocyte-derived dendritic cells. Spleen, mesenteric and axillary/cervical lymph node to body weight ratio were also significantly increased in Tlr5 −/−MRL/lpr mice compared to Tlr5 +/−and Tlr5 +/+littermates, with the effects more pronounced in fe malemice, suggesting that the deletion of Tlr5 impacted lymphoproliferation in addition to lupus nephritis. We are currently analyzing the lymphoid tissues to reveal potential cellular mechanisms. Notably, Tlr5 deficiency did not change the existing leaky gut in either female or male MRL/lpr mice. Future studies will elucidate the underlying mechanisms by which the deletion of Tlr5 modulates cellular functions to exacerbate lupus.