IGF-1 regulates astrocytic phagocytosis and inflammation through the p110¿ isoform of PI3K in a sex-specific manner
Insulin-like growth factor-I (IGF-I) signaling plays a key role in neuroinflammation. Here we show that IGF-1 also regulates phagocytosis of reactive astrocytes through p110¿ isoform of phosphatidylinositol 3-kinase (PI3K), differentially in both sexes. Systemic bacterial lipopolysaccharide (LPS)-tr...
| Autores: | , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/278498 |
| Acceso en línea: | http://hdl.handle.net/10261/278498 |
| Access Level: | acceso abierto |
| Palabra clave: | IGF-1 PI3K-isoforms Neuroinflammation Phagocytosis Sex differences |
| Sumario: | Insulin-like growth factor-I (IGF-I) signaling plays a key role in neuroinflammation. Here we show that IGF-1 also regulates phagocytosis of reactive astrocytes through p110¿ isoform of phosphatidylinositol 3-kinase (PI3K), differentially in both sexes. Systemic bacterial lipopolysaccharide (LPS)-treatment increased the expression of GFAP, a reactive astrocyte marker, in the cortex of mice in both sexes and was blocked by IGF-1 only in males. In primary astrocytes, LPS enhanced the mRNA expression of Toll-like receptors (TLR2,4) and proinflammatory factors: inducible nitric oxide synthase (iNOS), chemokine interferon-¿-inducible protein-10 (IP-10) and cytokines (IL-1ß, IL-6, and IL-10) in male and female. Treatment with IGF-1 counteracted TLR4 but not TLR2, iNOS, and IP10 expression in both sexes and cytokines expression in males. Furthermore, reactive astrocyte phagocytosis was modulated by IGF-1 only in male astrocytes. IGF-1 was also able to increase AKT-phosphorylation only in male astrocytes. PI3K inhibitors, AG66, TGX-221, and CAL-101, with selectivity toward catalytic p110¿, p110ß, and p110¿ isoforms respectively, reduced AKT-phosphorylation in males. All isoforms interact physically with IGF-1-receptor in both sexes. However, the expression of p110¿ is higher in males while the expression of IGF-1-receptor is similar in male and female. AG66 suppressed the IGF-1 effect on cytokine expression and counteracted the IGF-1-produced phagocytosis decrease in male reactive astrocytes. Results suggest that sex-differences in the effect of IGF-1 on the AKT-phosphorylation could be due to a lower expression of the p110¿ in female and that IGF-1-effects on the inflammatory response and phagocytosis of male reactive astrocytes are mediated by p110¿/PI3K subunit. |
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