title: Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease.
abstract: CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation. Sn+ microglia/macrophages associated with SMI32+ axonal spheroids and CD8+ T-lymphocytes. To analyze their pathogenic impact, we crossbred both models with Sn-deficient mice and scored axonal degeneration and neuronal integrity using immunohistochemistry, electron microscopy and optical coherence tomography. Degenerative alterations in the retinotectal pathway of Ppt1(-/-)Sn(-/-) and Cln3(-/-)Sn(-/-) mice were significantly reduced. Ppt1(-/-)Sn(-/-) mice also showed a substantially improved clinical phenotype and extended lifespan, attenuated numbers of M1-polarized microglia/macrophages and reduced expression levels of proinflammatory cytokines. This was accompanied by an increased frequency of CD8+CD122+ T-lymphocytes in the CNS of Ppt1(-/-)Sn(-/-) mice, the regulatory phenotype of which was demonstrated by impaired survival of CD8+CD122- effector T-lymphocytes in co-culture experiments. We show for the first time that increased Sn expression on microglia/macrophages contributes to neural perturbation in two distinct models of CLN disease. Our data also indicate that a rarely described CD8+CD122+ T-cell population can regulate the corresponding diseases. These studies provide insights into CLN pathogenesis and may guide in designing immuno-regulatory treatment strategies.
authors.affiliation: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Janos
authors.initials: J
authors.lastname: Groh
authors.affiliation: Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Eliana
authors.initials: E
authors.lastname: Ribechini
authors.affiliation: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Stadler
authors.affiliation: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schilling
authors.affiliation: Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.affiliation: Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000150:complications* / Q000473:pathology*; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D041623:Tomography, Optical Coherence
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; C102229:CLN3 protein, mouse; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D063267:Sialic Acid Binding Ig-like Lectin 1; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase
keywords: T-lymphocytes; immune regulation; microglia; neurodegeneration; neuroinflammation; neuronal ceroid lipofuscinosis