Microglia can exhibit different phenotypes that have some of the characteristics of M1- and M2-phenotypes, but they are also highly plastic cells and may transition between different states depending on both local and systemic influences.
...
The signalling of systemic inflammation to the CNS, arising as a consequence of injury or disease, is part of normal homeostasis; it takes place across an intact blood-brain barrier and does not lead to damage of the neurons of the CNS. Although most of what we know about signalling from the peripheral immune system to the brain has been studied in rodents, experimental studies in humans provide evidence for similar effects of systemic inflammation. LPS challenge in humans leads to fever and neuropsychological symptoms. For example, low-dose endotoxin in healthy volunteers reduced declarative memory performance that was inversely correlated with cytokine increases [
58] and increased symptoms of depression [
59].
Other clinical symptoms include fatigue and decrease in social interest. Similar findings have been described following influenza H1N1 virus infection; individuals reported symptoms of anxiety and depression up to 1 year after the infection [
60]. The use of biologicals as therapeutic agents has also provided valuable insight, and it is well known that peripheral injection of β-interferon leads to flu-like symptoms in patients with multiple sclerosis, that α-interferon therapy in patients with hepatitis C may lead to serious symptoms of depression in some individuals and that anti-tumour necrosis factor-α (anti-TNF) therapy in patients with psoriasis can lead to improvements in mood [
61]. There are likely multiple systemic inflammatory mediators that impact on innate immune cells in the CNS, leading to changes in behaviour.
The regulation of the microglia phenotype by the microenvironment of the CNS appears to be an important part of CNS immune physiology.
...
Most tissue macrophages, following the appropriate stimulus, can polarize into M1 and M2 or M2-like phenotypes [
66]. Classical activation and M1 polarization require interferon-γ (
IFN-γ) combined with
TLR4 signalling and are characterized by increased expression of pro-inflammatory mediators and effectors enabling phagocytosis and killing of pathogens. Alternative activation and M2 polarization occur in response to IL-4 and are distinguished by increased expression of transforming growth factor-β (TGFβ), IL-10, scavenger receptor CD206, MS4A4a/6A and fibrinogenic and coagulation factors, enabling regulation of wound healing, tissue repair, collagen formation and recruitment of Th2 cells. ...