Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system
IntroductionProgranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role o...
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Frontiers Media S.A.
2022-12-01
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author | Madelyn C. Houser Oihane Uriarte Huarte Oihane Uriarte Huarte Rebecca L. Wallings Rebecca L. Wallings Cody E. Keating Cody E. Keating Kathryn P. MacPherson Mary K. Herrick Mary K. Herrick George T. Kannarkat Sean D. Kelly Jianjun Chang Nicholas H. Varvel Jessica E. Rexach Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey |
author_facet | Madelyn C. Houser Oihane Uriarte Huarte Oihane Uriarte Huarte Rebecca L. Wallings Rebecca L. Wallings Cody E. Keating Cody E. Keating Kathryn P. MacPherson Mary K. Herrick Mary K. Herrick George T. Kannarkat Sean D. Kelly Jianjun Chang Nicholas H. Varvel Jessica E. Rexach Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey |
author_sort | Madelyn C. Houser |
collection | DOAJ |
description | IntroductionProgranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations.MethodsFirst, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT).ResultsMale PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner.DiscussionOur data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression. |
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spelling | doaj.art-4d8a321115ff4a7a8acb3699a6026cab2022-12-22T11:50:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10564171056417Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune systemMadelyn C. Houser0Oihane Uriarte Huarte1Oihane Uriarte Huarte2Rebecca L. Wallings3Rebecca L. Wallings4Cody E. Keating5Cody E. Keating6Kathryn P. MacPherson7Mary K. Herrick8Mary K. Herrick9George T. Kannarkat10Sean D. Kelly11Jianjun Chang12Nicholas H. Varvel13Jessica E. Rexach14Malú Gámez Tansey15Malú Gámez Tansey16Malú Gámez Tansey17Malú Gámez Tansey18Department of Physiology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United StatesCenter for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United StatesDepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United StatesCenter for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United StatesDepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United StatesCenter for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United StatesDepartment of Physiology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United StatesCenter for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United StatesDepartment of Physiology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Physiology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Physiology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neurology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, United StatesDepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United StatesCenter for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, United StatesNorman Fixel Institute for Neurodegenerative Disease, University of Florida Health, Gainesville, FL, United StatesEvelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, United StatesIntroductionProgranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations.MethodsFirst, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT).ResultsMale PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner.DiscussionOur data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1056417/fullprogranulinperipheral-brain crosstalkmicrogliamonocytesT cellsGPNMB |
spellingShingle | Madelyn C. Houser Oihane Uriarte Huarte Oihane Uriarte Huarte Rebecca L. Wallings Rebecca L. Wallings Cody E. Keating Cody E. Keating Kathryn P. MacPherson Mary K. Herrick Mary K. Herrick George T. Kannarkat Sean D. Kelly Jianjun Chang Nicholas H. Varvel Jessica E. Rexach Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey Malú Gámez Tansey Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system Frontiers in Immunology progranulin peripheral-brain crosstalk microglia monocytes T cells GPNMB |
title | Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system |
title_full | Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system |
title_fullStr | Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system |
title_full_unstemmed | Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system |
title_short | Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system |
title_sort | progranulin loss results in sex dependent dysregulation of the peripheral and central immune system |
topic | progranulin peripheral-brain crosstalk microglia monocytes T cells GPNMB |
url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1056417/full |
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