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Potential for Targeting Myeloid Cells in Controlling CNS Inflammation.

ABSTRACT: Multiple Sclerosis (MS) is characterized by immune cell infiltration to the central nervous system (CNS) as well as loss of myelin. Characterization of the cells in lesions of MS patients revealed an important accumulation of myeloid cells such as macrophages and dendritic cells (DCs). Data from the experimental autoimmune encephalomyelitis (EAE) model of MS supports the importance of peripheral myeloid cells in the disease pathology. However, the majority of MS therapies focus on lymphocytes. As we will discuss in this review, multiple strategies are now in place to target myeloid cells in clinical trials. These strategies have emerged from data in both human and mouse studies. We discuss strategies targeting myeloid cell migration, growth factors and cytokines, biological functions (with a focus on miRNAs), and immunological activities (with a focus on nanoparticles).

SUBMITTER: Ifergan I

PROVIDER: S-EPMC7573146 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Potential for Targeting Myeloid Cells in Controlling CNS Inflammation.

Ifergan Igal I Miller Stephen D SD

Frontiers in immunology 20201006

Multiple Sclerosis (MS) is characterized by immune cell infiltration to the central nervous system (CNS) as well as loss of myelin. Characterization of the cells in lesions of MS patients revealed an important accumulation of myeloid cells such as macrophages and dendritic cells (DCs). Data from the experimental autoimmune encephalomyelitis (EAE) model of MS supports the importance of peripheral myeloid cells in the disease pathology. However, the majority of MS therapies focus on lymphocytes. A ...[more]

PMID: 33123148

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Project description:Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity. Here, we found that Mir223 deficiency significantly ameliorated CNS inflammation, demyelination and the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and increased resting microglia and autophagy in brain microglial cells. In contrast, the autophagy inhibitor 3-methylademine (3-MA) aggravated the clinical symptoms of EAE in wild-type (WT) and Mir223-deficienct mice. Furthermore, it was confirmed that Mir223 deficiency in mice increased the protein expression of ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and LC3-II in bone marrow-derived macrophage cells compared with cells from WT mice. Indeed, the cellular level of Atg16l1 was decreased in BV2 cells upon Mir223 overexpression and increased following the introduction of antagomirs. We also showed that the 3' UTR of Atg16l1 contained functional Mir223-responsive sequences and that overexpression of ATG16L1 returned autophagy to normal levels even in the presence of Mir223 mimics. Collectively, these data indicate that Mir223 is a novel and important regulator of autophagy and that Atg16l1 is a Mir223 target in this process, which may have implications for improving our understanding of the neuroinflammatory process of EAE. Abbreviations: 3-MA: 3-methylademine; ACTB/?-actin: actin, beta; ATG: autophagy related; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CNR2: cannabinoid receptor 2 (macrophage); CNS: central nervous system; CQ: chloroquine; EAE: experimental autoimmune encephalomyelitis; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H&E: hematoxylin and eosin; ITGAM: integrin alpha M; LPS: lipoplysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; miRNAs: microRNAs; MS: multiple sclerosis; PPARG: peroxisome proliferator activated receptor gamma; PTPRC: protein tyrosine phosphatase, receptor type, C; RA: rheumatoid arthritis; SQSTM1: sequestosome 1; TB: tuberculosis; TIMM23: translocase of inner mitochondrial membrane 23; TLR: toll-like receptor.

Dataset Information

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation.

Publications

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation.

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