IGF-1 regulates neuroinflammation in a sex-specific manner

The systematic difference between individuals of different sexes within the same species is known as sexual dimorphism. According to previously published studies, glial cells react differently depending on the gender to inflammatory and neurodegenerative diseases. Specialized glial cells called astrocytes outnumber neurons by a factor of nearly five. They continuously tile the whole central nervous system (CNS) and perform a variety of crucial, intricate tasks in a functioning CNS. Astrocytes are important in how the nerve tissue reacts to injury. Astrocytes can perform neuroprotective actions by producing a number of trophic factors that support CNS recovery and repair, including insulin-like growth factor (IGF)-1. IGF-I is a neurotrophic hormone involved in various biological processes, including the control of neuroinflammation through the activation of the PI3K/Akt/CREB signaling pathway. Mammals express four class I PI3K catalytic isoforms (p110α, β, γ, and δ). The expression of the p110α, p110β, and p110δ proteins is widespread, whereas that of the p110γ protein is only seen in immune cells.

Although p110 isoforms regulate different physiological and pathological functions despite their high homology, it is yet unclear how PI3K isoforms contribute to neuroinflammation. In a recent study published in GLIA, spanish scientists, Daniel Pinto-Benito, Carmen Paradela-Leal, Danny Ganchala and Paula de Castro-Molina, led by Dr. Maria-Angeles Arevalo from Spanish National Research Council (Consejo Superior de Investigaciones Científicas (CSIC)) examined the mechanism underlying the effects of IGF-1 on reactive astrocytes and study which p110 isoform is responsible for the expression of inflammatory-associated genes and phagocytosis.

The research team found that systemic treatment of LPS causes an increase in GFAP expression in cortical astrocytes in both male and female mice. In addition, cotreatment with IGF-1 had no effect on females but restored baseline levels of GFAP expression in males. These findings compelled them to investigate the physiological and molecular mechanisms behind such sex disparities. The cerebral cortices of newborn male and female mice were used as the source of the primary astrocyte cultures used in the study, which were treated with LPS and IGF-1. According to the authors and using the new model, LPS significantly increased the mRNA expression of TLR2/4, iNOS, IP-10, IL-1β, IL-6, and IL-10 in astrocytes of both sexes. However, IGF-1 only prevented LPS from having changing the expression of IL-1, IL-6, and IL-10 in male astrocytes. Researchers’ revelation that IGF-1 does not have anti-inflammatory effects in females is indeed a novel finding. Because NF-κB signaling X-linked genes are highly expressed in females compared to males, therefore it was anticipated that IGF-1 is unable to counteract the inflammatory effects of LPS in females. When the authors looked at the primary female astrocytes culture they found they have higher basal phagocytic activity than male culture. Further, these studies also show that only in LPS-stimulated male astrocytes can IGF-1 counteract the effect of LPS on neural debris phagocytosis, which may be because IGF-1 signaling is different across the sexes. These findings demonstrate for the first time that, although female astrocytes have higher overall PI3K activity, male astrocytes have higher PI3K activation due to IGF-1. This action is also specific to IGF-1, as EGF, a known stimulator of AKT phosphorylation through PI3K activation, increased pAKT in both sexes.

In conclusion, Dr. Maria-Angeles Arevalo and her colleagues examined the impact of exogenous IGF-1 on reactive astrocyte phagocytosis and neuroinflammation and demonstrated that IGF-1 has a sex-specific effect in modifying neuroinflammation caused by LPS, lowering phagocytosis, and reducing the production of proinflammatory components in reactive male astrocytes. The new study successfully elaborated the mechanism showing that IGF-1 only reduces phagocytosis in males, probably to lessen the exaggerated reaction and that IGF-1’s actions were made accessible through activating the PI3K signaling pathway.