AUTHOR=Alajoleen Razan M. , Oakland David N. , Estaleen Rana , Shakeri Aida , Lu Ran , Appiah Michael , Sun Sha , Neumann Jonathan , Kawauchi Shimako , Cecere Thomas E. , McMillan Ryan P. , Reilly Christopher M. , Luo Xin M. 

TITLE=RETRACTED: Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1359534

DOI=10.3389/fimmu.2024.1359534

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>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).</p></sec><sec><title>Methods</title><p>We created MRL/<italic>lpr</italic> mice with global <italic>Tlr5</italic> deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.</p></sec><sec><title>Result</title><p>Contrary to our hypothesis that the deletion of <italic>Tlr5</italic> would attenuate lupus, our results showed exacerbation of lupus with <italic>Tlr5</italic> deficiency in female MRL/<italic>lpr</italic> mice. Remarkably higher levels of proteinuria were observed in <italic>Tlr5</italic><sup>-/-</sup> MRL/<italic>lpr</italic> mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and <italic>Tlr5</italic> deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, <italic>Tlr5</italic> deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5<sup>-/-</sup> MRL/<italic>lpr</italic> mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with <italic>Tlr5</italic> deletion. Notably, <italic>Tlr5</italic> deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota.</p></sec><sec><title>Conclusion</title><p>Global deletion of <italic>Tlr5</italic> exacerbates lupus-like disease in MRL/<italic>lpr</italic> mice. Future studies will elucidate the underlying mechanisms by which <italic>Tlr5</italic> deficiency modulates host-microbiota interactions to exacerbate lupus.</p></sec>