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.
Highlights
Insulin-like growth factor-1 (IGF-1) is a protein produced in several organs, such as gonads, muscle, bones, liver, gut and brain and is present in plasma
IGF-1 is actively transported to the central nervous system (CNS) from plasma through the choroid plexus (Carro et al, 2000; Santi et al, 2017), and it is locally produced in the brain by neurons and glial cells (Quesada et al, 2007; Suh et al, 2013; Rodriguez-Perez et al, 2016)
Actions of IGF-1 may be context-dependent (Fernandez and Torres-Alemán, 2012), and IGF-1 may be involved in inflammation in a context-dependent mode, which may explain controversial results on the role of IGF-1 in neuroinflammation
Summary
Insulin-like growth factor-1 (IGF-1) is a protein produced in several organs, such as gonads, muscle, bones, liver, gut and brain and is present in plasma. Since AII/AT1R activity is enhanced in the nigra of aged rats (Villar-Cheda et al, 2012, 2014), a counterregulatory increase rather than a decrease in IGF-1 levels may be expected This suggests an aging-related loss of the IGF1-mediated counterregulatory mechanism, which may lead to the pro-oxidative and pro-inflammatory state observed aged brains (Villar-Cheda et al, 2012; Lee et al, 2013). In addition to IGF-1-induced neuronal protection by modulation of the microglial inflammatory response, IGF-1 mediate a direct effect on neurons (see above), which may lead to indirect (i.e., neuron-mediated) modulation of the glial inflammatory response This is consistent with our recent studies on the intraneuronal or intracrine RAS, in which we observed that activation of nuclear AT1R induces several intraneuronal protective mechanisms that may counteract the deleterious effects of activation of plasmatic membrane pro-oxidative AT1R (Valenzuela et al, 2016; Villar-Cheda et al, 2017). This intracrine protective response was impaired in nuclei isolated from aged brains (Villar-Cheda et al, 2017)
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