Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model
IntroductionLeaky 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 activati...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1359534/full |
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| author | Razan M. Alajoleen David N. Oakland Rana Estaleen Aida Shakeri Ran Lu Michael Appiah Sha Sun Jonathan Neumann Shimako Kawauchi Thomas E. Cecere Ryan P. McMillan Christopher M. Reilly Xin M. Luo |
| author_facet | Razan M. Alajoleen David N. Oakland Rana Estaleen Aida Shakeri Ran Lu Michael Appiah Sha Sun Jonathan Neumann Shimako Kawauchi Thomas E. Cecere Ryan P. McMillan Christopher M. Reilly Xin M. Luo |
| author_sort | Razan M. Alajoleen |
| collection | DOAJ |
| description | IntroductionLeaky 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).MethodsWe created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.ResultContrary 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.ConclusionGlobal 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. |
| first_indexed | 2024-03-08T09:36:16Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T09:36:16Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e0ef88a8a34d4fdc9a82a8111be4317d2024-01-30T08:53:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011510.3389/fimmu.2024.13595341359534Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse modelRazan M. Alajoleen0David N. Oakland1Rana Estaleen2Aida Shakeri3Ran Lu4Michael Appiah5Sha Sun6Jonathan Neumann7Shimako Kawauchi8Thomas E. Cecere9Ryan P. McMillan10Christopher M. Reilly11Xin M. Luo12Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesGraduate Program of Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biological Sciences, College of Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United StatesTransgenic Mouse Facility, University of California, Irvine, Irvine, CA, United StatesTransgenic Mouse Facility, University of California, Irvine, Irvine, CA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesDepartment of Biomedical Sciences, Edward Via College of Osteopathic Medicine, Blacksburg, VA, United StatesDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United StatesIntroductionLeaky 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).MethodsWe created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.ResultContrary 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.ConclusionGlobal 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1359534/fulllupusTLR5glomerulonephritislymphoproliferationgut microbiota |
| spellingShingle | Razan M. Alajoleen David N. Oakland Rana Estaleen Aida Shakeri Ran Lu Michael Appiah Sha Sun Jonathan Neumann Shimako Kawauchi Thomas E. Cecere Ryan P. McMillan Christopher M. Reilly Xin M. Luo Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model Frontiers in Immunology lupus TLR5 glomerulonephritis lymphoproliferation gut microbiota |
| title | Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model |
| title_full | Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model |
| title_fullStr | Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model |
| title_full_unstemmed | Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model |
| title_short | Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model |
| title_sort | tlr5 deficiency exacerbates lupus like disease in the mrl lpr mouse model |
| topic | lupus TLR5 glomerulonephritis lymphoproliferation gut microbiota |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1359534/full |
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