학술논문
Tlr5 deficiency exacerbates lupus-like disease in the MRL/ lpr mouse model.
Document Type
Academic Journal
Author
Alajoleen RM; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Oakland DN; Graduate Program of Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United States.; Estaleen R; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Shakeri A; Department of Biological Sciences, College of Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Lu R; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Appiah M; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Sun S; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States.; Neumann J; Transgenic Mouse Facility, University of California, Irvine, Irvine, CA, United States.; Kawauchi S; Transgenic Mouse Facility, University of California, Irvine, Irvine, CA, United States.; Cecere TE; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; McMillan RP; Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.; Reilly CM; Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine, Blacksburg, VA, United States.; Luo XM; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
Subject
Language
English
Abstract
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/ lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.
Result: Contrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/ lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5-/- MRL/ lpr mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and Tlr5 deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, Tlr5 deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5 -/- MRL/ lpr mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with Tlr5 deletion. Notably, Tlr5 deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota.
Conclusion: Global deletion of Tlr5 exacerbates lupus-like disease in MRL/ lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Alajoleen, Oakland, Estaleen, Shakeri, Lu, Appiah, Sun, Neumann, Kawauchi, Cecere, McMillan, Reilly and Luo.)
Methods: We created MRL/ lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.
Result: Contrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/ lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5
Conclusion: Global deletion of Tlr5 exacerbates lupus-like disease in MRL/ lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Alajoleen, Oakland, Estaleen, Shakeri, Lu, Appiah, Sun, Neumann, Kawauchi, Cecere, McMillan, Reilly and Luo.)