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Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

ABSTRACT: Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration.

SUBMITTER: Tolentino MJ

PROVIDER: S-EPMC10747662 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

Tolentino Michael J MJ Tolentino Andrew J AJ Tolentino Elizabeth M EM Krishnan Anitha A Genead Mohamed A MA

Pharmaceuticals (Basel, Switzerland) 20231216 12

Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained ...[more]

PMID: 38139861

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Project description:Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes α-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the SIGLEC11 gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer’s disease, although its role in inflammation and neurodegeneration remains poorly understood. In this study, aged Siglec-11 transgenic (tg) mice, which expressed the human SIGLEC-11 receptor on microglia and tissue macrophages, were investigated. The brains of the Siglec-11 tg mice were analyzed in 6-month-old mature mice and 24-month-old aged mice using immunohistochemistry and transcriptomics. Results showed decreased density and fewer clusters of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells in the hippocampus and substantia nigra, as well as less lipid-laden microglia in the Siglec-11 tg in comparison to wildtype (WT) controls. Additionally, Siglec-11 tg mice exhibited less age-related neuronal loss in the substantia nigra pars compacta in comparison to WT mice. Transcriptome analysis revealed suppression of oxidative phosphorylation and inflammatory pathways in Siglec-11 tg brains at 6 months, with further suppression of complement and coagulation cascades at 24 months of age in comparison to WT mice. Gene transcript levels of the pro-inflammatory cytokines tumor necrosis factor alpha (Tnf) and interleukin 1 beta (Il-1b), as well as the oxidative stress markers cytochrome b-245 alpha and beta (Cyba and Cybb) and the nitric oxide synthase 2 (Nos2) were reduced in the brains of 24-month-old Siglec-11 tg mice relative to WT controls. Brains of 24-month-old Siglec-11 tg mice also exhibited lower gene transcription of complement component 4 and integrin alpha M (C4 and Itgam), along with the complement C1q subcomponents a and c (C1qa and C1qc). In summary, aged Siglec-11 tg mice displayed reduced brain inflammation and oxidative stress, as well as protection against age-related neuronal loss in the substantia nigra.

Project description:ImportanceSialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a novel immune checkpoint molecule that is highly homologous to programmed cell death ligand 1 (PD-L1), but information remains limited about its role in esophageal squamous cell carcinoma (ESCC).ObjectiveTo explore the expression pattern and association of Siglec-15 with outcomes among patients with ESCC who received neoadjuvant chemoradiotherapy (CRT).Design, setting, and participantsThis retrospective cohort study was conducted at an academic institution in China. Participants included patients with ESCC who underwent neoadjuvant CRT and esophagectomy between June 2002 and December 2018. Multiplexed immunofluorescence staining was used to evaluate the expression of Siglec-15 and PD-L1 in tumor cells (TCs) or tumor-associated macrophages based on pre-CRT biopsies. Different immune phenotypes have been proposed and further validated in an independent cohort. Data analysis was conducted from January to May 2021.ExposuresSiglec-15 or PD-L1 positivity vs negativity.Main outcomes and measuresPathologic complete response (pCR), overall survival (OS), and recurrence-free survival (RFS).ResultsOf 130 participants (median [range] age, 56 [42-73] years; 108 [83.1%] male participants) in the primary cohort, 58 patients (44.6%) achieved a pCR after neoadjuvant CRT. Siglec-15 and PD-L1 were detected in both TCs and macrophages. The percentage of Siglec-15-positive macrophages was notably higher than that of Siglec-15-positive TCs (median [IQR]: 34.4% [12.7%-64.3%] vs 4.8% [0.7%-25.6%]; P < .001). TC-Siglec-15 expression was significantly and positively associated with macrophage-Siglec-15 expression (r = 0.78; P < .001). Siglec-15 positivity was significantly associated with a higher rate of pCR (37 of 70 [52.9%] vs 21 of 60 [35.0%]; P = .04), more favorable OS (hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01), and RFS (HR, 0.48; 95% CI, 0.26-0.88; P = .02). However, PD-L1 positivity in TCs was negatively associated with survival. Stratification analysis further revealed that patients with combined Siglec-15 positivity and PD-L1 negativity had better survival than those with other phenotypes. Major findings were reproducible in a validation cohort with 55 patients.Conclusions and relevanceIn this cohort study of patients with ESCC receiving neoadjuvant CRT, Siglec-15 positivity was associated with a better pathological response and more favorable survival. Siglec-15 could serve as a novel biomarker to identify potential candidates that may benefit from immunotherapy combined with CRT.

Dataset Information

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

Publications

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

Similar Datasets

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