IGF‐1 regulates astrocytic phagocytosis and inflammation through the p110α isoform of PI3K in a sex‐specific manner

Abstract

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 p110α 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‐γ‐inducible protein‐10 (IP‐10) and cytokines (IL‐1β, 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 p110α, p110β, and p110δ isoforms respectively, reduced AKT‐phosphorylation in males. All isoforms interact physically with IGF‐1‐receptor in both sexes. However, the expression of p110α 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 p110α in female and that IGF‐1‐effects on the inflammatory response and phagocytosis of male reactive astrocytes are mediated by p110α/PI3K subunit.

Microglial CD11b Knockout Contributes to Axonal Debris Clearance and Axonal Degradation Attenuation via IGF-1 After Acute Optic Nerve Injury

“…However, IGF-1 does not change the phagocytic ability of M1-type or resting-state (M0) microglia. The selectivity of IGF-1 phagocytosis regulation was also reported by Pinto-Benito et al 34 Based on these results, we suggest that M2-type microglia may have a unique phagocytic pathway regulated by IGF-1.…”

“…The effect of IGF-1 on phagocytosis has been reported. 34 , 46 Nevertheless, to our knowledge, the present study is the first to report the role of IGF-1 on M2-type microglia phagocytosis. We found that CD11b knockdown resulted in further elevation of IGF-1 secretion by M2 microglia.…”

“…IGF-1 has been reported to be involved in the phagocytosis of a variety of cells. 33 , 34 Does IGF-1 promote microglial phagocytosis? IGF-1 is a secreted protein.…”

Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

“…This endothelin motif is operating in a complex environment, in which the inflammatory component given by IFN‐gamma and IL‐6 signals, overlap with the production of IGF‐1 (see Figure 6a). The IGF‐1 acts as growth‐modulator, differentiation factor and neuroprotective molecule (Pinto‐Benito et al, 2022; Prabhu et al, 2019). The enhanced significance of the ‘endothelins signalling’ in the MCI group seems to be an adaptive response to balance the diminution of this vasoactive peptide observed in the eldered group (FDR Younger = 2 × 10 −11 , FDR Eldered = 1.2 × 10 −5 , FDR MCI = 1.2 × 10 −9 ).…”

Hyperbaric Oxygen Therapy Promotes Hearing Gain with Increases in Serum IGF-1 and HSP70 in Patients with Idiopathic Sudden Sensorineural Hearing Loss

“…Some evidence suggests that IGF-1 inhibits TLR4 and NF- κ B signaling. Pinto–Benito et al [ 30 ] found that IGF-1 treatment counteracted TLR4 expression in males. Based on in vitro experiments , IGF-1 might serve as a potential therapeutic target for cirrhosis and intestinal barrier dysfunction via its inactivation of the TLR4/MyD88/NF- κ B pathway [ 31 ].…”