IGF-1 regulates astrocytic phagocytosis and inflammation through the p110 alpha 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 alpha 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-gamma-inducible protein-10 (IP-10) and cytokines (IL-1 beta, 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 alpha, p110 beta, and p110 delta isoforms respectively, reduced AKT-phosphorylation in males. All isoforms interact physically with IGF-1-receptor in both sexes. However, the expression of p110 alpha 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 alpha in female and that IGF-1-effects on the inflammatory response and phagocytosis of male reactive astrocytes are mediated by p110 alpha/PI3K subunit.

Automated summary

IGF-1 regulates phagocytosis and inflammatory response of reactive astrocytes differently in males and females through the p110 alpha isoform of PI3K.