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CD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen species

Yeo, YA;Martínez Gómez, JM;Croxford, JL;Gasser, S;Ling, EA;Schwarz, H;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the murine microglia cell lines BV-2 and N9, as well as primary murine microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established murine model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kill oligodendrocytes.

PubMed ID: 22799524
231323132017-06-052017-06-0511:03:0111:03:012018-03-092018-03-0911:13:0411:13:04Yeo, YA;Martínez Gómez, JM;Croxford, JL;Gasser, S;Ling, EA;Schwarz, H;Yeo, YA;Martínez Gómez, JM;Croxford, JL;Gasser, S;Ling, EA;Schwarz, H;20122012CD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen speciesCD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen speciesJournal Of NeuroinflammationJournal Of Neuroinflammation173173992279952422799524

CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the murine microglia cell lines BV-2 and N9, as well as primary murine microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established murine model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kill oligodendrocytes.

CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the murine microglia cell lines BV-2 and N9, as well as primary murine microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established murine model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kill oligodendrocytes.

4.9024.902

EAE induction:

... CD137L-/- mice were a gift from Amgen and bred in-house under pathogen-free conditions. Mice were injected subcutaneously with 100 μg of myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55) (Sigma-Aldrich) and 1 mg heat-killed Mycobacterium tuberculosis H37RA (Difco) emulsified in complete Freund’s adjuvant. Pertussis toxin (200 ng in PBS; List Biological Laboratories) was injected intraperitoneally on days 0 and 2 after immunization. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

EAE induction:

... CD137L-/- mice were a gift from Amgen and bred in-house under pathogen-free conditions. Mice were injected subcutaneously with 100 μg of myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55) (Sigma-Aldrich) and 1 mg heat-killed Mycobacterium tuberculosis H37RA (Difco) emulsified in complete Freund’s adjuvant. Pertussis toxin (200 ng in PBS; List Biological Laboratories) was injected intraperitoneally on days 0 and 2 after immunization. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-173https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-1732012-07-162012-07-1610.1186/1742-2094-9-17310.1186/1742-2094-9-173Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Bufferyeoyee@nus.edu.sgyeoyee@nus.edu.sgActivated;Activation;Adhesion;Adjuvant;Antigen;APC;Apoptosis;Autoimmune;Biological;Cell;Central Nervous System;Clinical;CNS;Culture;Demonstrate;Disease;EAE;Encephalomyelitis;Experimental;Experimental Autoimmune Encephalomyelitis;Expressed;Factor;In vitro;Induction;Kill;List;List Biological;Mechanism;Molecule;MS;Murine;Necrosis;Neuroinflammation;Pathogenic;Pertussis;Potent;Protein;Receptor;Soluble;Study;T cell;TNF;Toxin;Transmembrane;Tumor;Journal Of NeuroinflammationActivated;Activation;Adhesion;Adjuvant;Antigen;APC;Apoptosis;Autoimmune;Biological;Cell;Central Nervous System;Clinical;CNS;Culture;Demonstrate;Disease;EAE;Encephalomyelitis;Experimental;Experimental Autoimmune Encephalomyelitis;Expressed;Factor;In vitro;Induction;Kill;List;List Biological;Mechanism;Molecule;MS;Murine;Necrosis;Neuroinflammation;Pathogenic;Pertussis;Potent;Protein;Receptor;Soluble;Study;T cell;TNF;Toxin;Transmembrane;Tumor;Journal Of Neuroinflammation180180cd137-ligand-activated-microglia-inducescd137-ligand-activated-microglia-induces