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...

Full description

Bibliographic Details
Main Authors: Madelyn C. Houser, Oihane Uriarte Huarte, Rebecca L. Wallings, Cody E. Keating, Kathryn P. MacPherson, Mary K. Herrick, George T. Kannarkat, Sean D. Kelly, Jianjun Chang, Nicholas H. Varvel, Jessica E. Rexach, Malú Gámez Tansey
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-12-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2022.1056417/full
_version_ 1797979300896440320
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.
first_indexed 2024-04-11T05:36:50Z
format Article
id doaj.art-4d8a321115ff4a7a8acb3699a6026cab
institution Directory Open Access Journal
issn 1664-3224
language English
last_indexed 2024-04-11T05:36:50Z
publishDate 2022-12-01
publisher Frontiers Media S.A.
record_format Article
series Frontiers in Immunology
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
work_keys_str_mv AT madelynchouser progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT oihaneuriartehuarte progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT oihaneuriartehuarte progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT rebeccalwallings progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT rebeccalwallings progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT codyekeating progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT codyekeating progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT kathrynpmacpherson progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT marykherrick progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT marykherrick progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT georgetkannarkat progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT seandkelly progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT jianjunchang progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT nicholashvarvel progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT jessicaerexach progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT malugameztansey progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT malugameztansey progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT malugameztansey progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem
AT malugameztansey progranulinlossresultsinsexdependentdysregulationoftheperipheralandcentralimmunesystem