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While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11\u2013HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11\u2013HSP, including examination of three human <jats:italic>postmortem<\/jats:italic> brain donations, immunophenotyping of patients\u2019 peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11\u2013HSP. Neuropathological analysis of SPG11\u2013HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1<jats:sup>+<\/jats:sup> cells. In a larger cohort of SPG11\u2013HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFN\u03b3 led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFN\u03b3-mediated immune hyperactivation and <jats:italic>SPG11<\/jats:italic> loss of function. STAT1 expression was increased both in human <jats:italic>postmortem<\/jats:italic> brain tissue and in an <jats:italic>Spg11<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11\u2013HSP patients and constitute the first description of myeloid cell\/ microglia activation in human SPG11\u2013HSP. IFN\u03b3\/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon <jats:italic>SPG11<\/jats:italic> loss of function indicate that immunomodulation strategies may slow down disease progression.<\/jats:p>","DOI":"10.1007\/s00401-023-02675-w","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T16:02:24Z","timestamp":1706889744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients"],"prefix":"10.1007","volume":"147","author":[{"given":"Laura","family":"Krumm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Pozner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naime","family":"Zagha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Coras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanos","family":"Tsaktanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Scherpelz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Y.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Kaindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Stolzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"S\u00fc\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukhran","family":"Khundadze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian A.","family":"H\u00fcbner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus J.","family":"Riemenschneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Baets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veit","family":"Rothhammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Krach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Winner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2172-7386","authenticated-orcid":false,"given":"Martin","family":"Regensburger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"2675_CR1","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1167\/IOVS.17-23266","volume":"59","author":"N Asano","year":"2018","unstructured":"Asano N, Hampel U, Garreis F, Schr\u00f6der A, Schicht M, Hammer CM et al (2018) Differentiation patterns of immortalized human meibomian gland epithelial cells in three-dimensional culture. 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