deficiency exacerbates lupus-like disease in the MRL/ mouse model.

Introduction: Leaky gut has been linked to autoimmune disorders including lupus. We previously reported upregulation of anti-flagellin antibodies in the blood of lupus patients and lupus-prone mice, which led to our hypothesis that a leaky gut drives lupus through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5).

Methods: We created MRL/ mice with global deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.

Result: Contrary to our hypothesis that the deletion of would attenuate lupus, our results showed exacerbation of lupus with deficiency in female MRL/ mice. Remarkably higher levels of proteinuria were observed in MRL/ mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition,  deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5 MRL/ mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with deletion. Notably, deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota.

Conclusion: Global deletion of exacerbates lupus-like disease in MRL/ mice. Future studies will elucidate the underlying mechanisms by which deficiency modulates host-microbiota interactions to exacerbate lupus.