Biology subjects

Alkhimovitch, A.

Publications and source records attributed to Alkhimovitch, A..

3 recordsLinked to original sources

bioRxiv2026

Dual Role of Ninjurin-1 in Myeloid Cell Adhesion and Inflammation in Relapse-Remitting EAE

Nerve Injury-Induced Protein 1 (Ninjurin-1) is an adhesion molecule implicated in inflammation and tissue injury, yet its role in neuroinflammatory diseases such as multiple sclerosis (MS) remains poorly defined. Here, we identify Ninjurin-1 as a key mediator of immune activation and CNS infiltration in relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), a model of relapsing-remitting MS (RRMS). Using flow cytometry, gene-expression profiling, and in vivo peptide blockade, we show that Ninjurin-1 is markedly upregulated on CNS-infiltrating myeloid cells during disease progression. Ninjurin-1 myeloid cells display a dual function, as both an adhesion molecule and a marker of inflammatory activation, characterized by increased antigen presentation, cytokine production, and transcriptional enrichment for genes regulating adhesion, migration, and innate immune signaling. Importantly, therapeutic blockade of Ninjurin-1 significantly reduced clinical severity, CNS immune infiltration, and demyelination in RR-EAE. These findings uncover a previously unrecognized role for Ninjurin-1 in myeloid-driven neuroinflammation and highlight its potential as a therapeutic target for relapsing-remitting MS.

neuroscience↗

bioRxiv2025

Wnt-Activated Immunoregulatory Myeloid Cells Prevent Relapse in Experimental Autoimmune Encephalomyelitis and Offer a Potential Therapeutic Strategy for Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by recurrent inflammatory relapses and neurodegeneration. Myeloid cells play a critical role in shaping the inflammatory environment and influencing disease progression. Here, we demonstrate that activation of the Wnt signaling pathway reprograms myeloid cells into an immunoregulatory phenotype, leading to reduced neuroinflammation and disease severity. Using both experimental autoimmune encephalomyelitis (EAE) and human-derived myeloid cells, we show that Wnt agonist treatment promotes the expression of inhibitory molecules such as PD-L1 and PD-L2, suppressing pro-inflammatory responses. In the chronic and relapsing-remitting EAE models, Wnt activation significantly reduced disease severity, immune cell infiltration into the CNS, and pathogenic T cell responses. Notably, in relapsing-remitting EAE, Wnt treatment prevented new relapses in a PD-L1-dependent manner, highlighting the crucial role of myeloid cell-mediated immune regulation. These findings reveal a previously unrecognized role for Wnt signaling in myeloid cell immunoregulation and suggest that targeting this pathway could provide a novel therapeutic strategy for MS and other autoimmune diseases.

immunology↗

bioRxiv2023

Microglia-derived TGF-β1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain

While TGF-{beta} signaling is essential for microglial function, the cellular source of TGF-{beta} ligand and its spatial regulation remains unclear in the adult CNS. Our data support that microglia, not astrocytes or neurons, are the primary producers of TGF-{beta}1 ligands needed for microglial homeostasis. Microglia (MG)-Tgfb1 inducible knockout (iKO) leads to the activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-{beta}1 ligands are important in the adult CNS. Interestingly, astrocytes in MG-Tgfb1 iKO mice show a transcriptome profile that closely aligns with A1-like astrocytes. Additionally, using sparse mosaic single-cell microglia iKO of TGF-{beta}1 ligand, we established an autocrine mechanism for TGF-{beta} signaling. Importantly MG-Tgfb1 iKO mice show cognitive deficits, supporting that precise spatial regulation of TGF-{beta}1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

neuroscience↗