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However, the functional impacts of up-regulated GPNMB are currently unknown, and it is currently unclear if targeting GPNMB will be protective or deleterious. Increases in GPNMB seen in FTD-<jats:italic>GRN<\/jats:italic> are reproduced in brains of aged <jats:italic>Grn<\/jats:italic>-deficient mice. Importantly, although brains of young <jats:italic>Grn<\/jats:italic>-deficient mice do not exhibit upregulated Gpnmb expression, peripheral immune cells of these mice exhibit increased Gpnmb expression as young as 5-to-6\u00a0months, suggesting the effects of <jats:italic>Grn<\/jats:italic>-deficiency in the periphery proceed those in the brain. <jats:italic>Grn<\/jats:italic>-deficiency is known to alter peripheral immune cell function, including impaired autophagy and altered cytokine secretion. GPNMB has potential effects on these processes, but has never been studied in peripheral immune cells of patients or preclinical models. Informing the functional significance of GPNMB upregulation in <jats:italic>Grn<\/jats:italic>-deficient states in myeloid cells has potential to inform GPNMB as a therapeutic candidate.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-<jats:italic>GRN<\/jats:italic> patients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (<jats:italic>Grn\u00a0-\/-<\/jats:italic>) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>ASO-mediated knock-down of <jats:italic>GPNMB<\/jats:italic> increased lysosomal burden and IL1\u03b2 cytokine secretion in FTD-<jats:italic>GRN<\/jats:italic> carriers and NHCs monocytes. ASO-mediated knock-down of <jats:italic>Gpnmb<\/jats:italic> in <jats:italic>Grn<\/jats:italic>-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation. In addition, ASO-mediated knock-down of <jats:italic>Gpnmb<\/jats:italic> increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages from <jats:italic>Grn<\/jats:italic>-deficient females. Finally, ASO-mediated knock-down of <jats:italic>Gpnmb<\/jats:italic> dysregulated IFN<jats:inline-formula>\n                <jats:alternatives>\n                  <jats:tex-math>$$\\gamma$$<\/jats:tex-math>\n                  <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                    <mml:mi>\u03b3<\/mml:mi>\n                  <\/mml:math>\n                <\/jats:alternatives>\n              <\/jats:inline-formula>-stimulated IL6 cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the Gpnmb extracellular fragment (ECF).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our data herein reveal that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells, potentially via secretion of its ECF. Therefore, in progranulin-deficient states, the marked upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion of GPNMB in FTD-<jats:italic>GRN<\/jats:italic> would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions mediated by GPNMB. Specifically, our data indicate that therapeutic strategies inhibiting GPNMB levels and\/or activity may worsen the effects of GRN deficiency.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13024-025-00829-w","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T17:46:44Z","timestamp":1744134404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses"],"prefix":"10.1186","volume":"20","author":[{"given":"Rebecca L.","family":"Wallings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew A.","family":"Gillett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah A.","family":"Staley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savanna","family":"Mahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Mark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle","family":"Neighbarger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Kordasiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren D.","family":"Hirst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mal\u00fa G\u00e1mez","family":"Tansey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"issue":"9","key":"829_CR1","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/nsb0996-747","volume":"3","author":"R Hrabal","year":"1996","unstructured":"Hrabal R, et al. 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All patient samples were obtained from NCRAD (see funding details below), and all participants provided informed consent in their respective cohort studies. This study was reviewed and approved by the University of Florida Institutional Animal Care and Use Committee (IACUC202200000114).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MGT is a current or recent advisor\/consultant for INmune Bio, Merck, Alnylam, Astex Pharmaceuticals, Arvinas, Therapeutics, Forward Therapeutics, Weston Foundation, Alzheimer\u2019s Association, Bright Focus Foundation, New Horizons Research, SciNeuro, NysnoBio, Longevity, Longeveron, iMetabolic Pharma, Novo Nordisk, Cellestial Health, iMMvention and Jaya. MGT is EIC for NPJ Parkinson\u2019s Disease. WDH is an employee of Biogen and HK is an employee of Ionis Pharmaceuticals where ASOs are currently under development for neurological indications. All other authors hold no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41"}}