Insulin-Like Growth Factor-1 and Neuroinflammation

Abstract

Insulin-like growth factor-1 (IGF-1) effects on aging and neurodegeneration is still controversial. However, it is widely admitted that IGF-1 is involved in the neuroinflammatory response. In peripheral tissues, several studies showed that IGF-1 inhibited the expression of inflammatory markers, although other studies concluded that IGF-1 has proinflammatory functions. Furthermore, proinflammatory cytokines such as TNF-α impaired IGF-1 signaling. In the brain, there are controversial results on effects of IGF-1 in neuroinflammation. In addition to direct protective effects on neurons, several studies revealed anti-inflammatory effects of IGF-1 acting on astrocytes and microglia, and that IGF-1 may also inhibit blood brain barrier permeability. Altogether suggests that the aging-related decrease in IGF-1 levels may contribute to the aging-related pro-inflammatory state. IGF-1 inhibits the astrocytic response to inflammatory stimuli, and modulates microglial phenotype (IGF-1 promotes the microglial M2 and inhibits of M1 phenotype). Furthermore, IGF-1 is mitogenic for microglia. IGF-1 and estrogen interact to modulate the neuroinflammatory response and microglial and astrocytic phenotypes. Brain renin-angiotensin and IGF-1 systems also interact to modulate neuroinflammation. Induction of microglial IGF-1 by angiotensin, and possibly by other pro-inflammatory inducers, plays a major role in the repression of the M1 microglial neurotoxic phenotype and the enhancement of the transition to an M2 microglial repair/regenerative phenotype. This mechanism is impaired in aged brains. Aging-related decrease in IGF-1 may contribute to the loss of capacity of microglia to undergo M2 activation. Fine tuning of IGF-1 levels may be critical for regulating the neuroinflammatory response, and IGF-1 may be involved in inflammation in a context-dependent mode.

Keywords: IGF-1; aging; angiotensin; astrocytes; estrogen; insulin; microglia; neurodegeneration.

Figure 1

Schematic model showing the possible role of Insulin-like growth factor-1 (IGF-1) in neuroinflammation. IGF-1 is actively transported from plasma and locally produced in the brain by neurons and glial cells (blue arrows). Microglial cells are a major source of IGF-1(blue arrow) in comparison with astrocytes and neurons (dashed blue arrows). IGF-1 receptors are predominantly expressed in neurons and astrocytes, which appear to be targeted by IGF-1 in lesioned regions. IGF-1 promotes neuronal survival and the M2 microglial repair/regenerative phenotype (green arrows), and inhibits the astrocytic response to inflammatory stimuli and the M1 microglial phenotype (red arrows). Therefore, IGF-1 induces repression of the M1 microglial neurotoxic phenotype and enhancement of the transition to M2 (black arrow). Aging-related decrease in IGF-1 may contribute to the loss of capacity of microglia to undergo M2 activation, leading to an aging-related pro-inflammatory state. Brain IGF-1, estrogen and angiotensin interact to modulate the neuroinflammatory response. However, these regulatory mechanisms are impaired in aged brains. Abbreviations: BBB, blood-brain barrier; E2, estrogen; RAS, renin-angiotensin system. Figure was produced using Servier Medical Art (http://www.servier.com).