Universität zu Köln

Tabel, Mona, Wolf, Anne ORCID: 0000-0003-2551-9821, Szczepan, Manon, Xu, Heping ORCID: 0000-0003-4000-931X, Jaegle, Herbert, Moehle, Christoph, Chen, Mei and Langmann, Thomas ORCID: 0000-0001-6826-529X (2022). Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration. J. Neuroinflamm., 19 (1). LONDON: BMC. ISSN 1742-2094

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Abstract

Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a beta-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and Cx3cr1(GFP/+) mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and Cx3cr1(GFP/+) mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tabel, Mona UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Anne UNSPECIFIED orcid.org/0000-0003-2551-9821 UNSPECIFIED Szczepan, Manon UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Heping UNSPECIFIED orcid.org/0000-0003-4000-931X UNSPECIFIED Jaegle, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Moehle, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Mei UNSPECIFIED UNSPECIFIED UNSPECIFIED Langmann, Thomas UNSPECIFIED orcid.org/0000-0001-6826-529X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-678833
DOI:	10.1186/s12974-022-02589-6
Journal or Publication Title:	J. Neuroinflamm.
Volume:	19
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1742-2094
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MACULAR DEGENERATION; LUNG FIBROSIS; ACTIVATION; IMPAIRMENT; CELLS Multiple languages Immunology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67883