The brain contains its own set of cells, including immune cells like microglia. Microglia are the macrophages of the brain. Like macrophages of the rest of the body, microglia are able to recognize invading pathogens and promote inflammation. A common stimulant of infection is lipopolysaccharide (LPS), a component of Gram negative bacterial cell walls that can induce septic shock. Initially, LPS exposure to macrophages induces production of pro-inflammatory cytokines; these pro-inflammatory macrophages are known as M1 macrophages. Typically, this initial wave of LPS primes the immune system, making the immune response more robust upon subsequent waves of LPS. However, localized tissue damage can result from inflammation and must be avoided in the brain. Therefore, microglia must balance the bactericidal inflammatory response with neurological protection.
Like macrophages, microglia will also promote inflammation when stimulated with an initial wave LPS. In contrast with macrophages, additional waves of LPS do not promote further inflammation. Instead of being primed for further infection, microglia will undergo a state of tolerance where additional waves of infection stops the production of pro-inflammatory cytokines and induces the production of anti-inflammatory cytokines. These anti-inflammatory macrophages/microglia are known as M2 and promote wound healing and tissue repair. The shift from M1 to M2 microglia helps to protect the brain from damage stemming from prolonged inflammation. Despite knowing that microglia switch from M1 to M2 macrophages with multiple waves of LPS, the molecular switch responsible was previously unknown.
In a study conducted by Ajmone-Cat et al., a key regulator responsible for microglial tolerance towards repeated LPS exposure was shown to be is the glycogen synthase kinase 3 (GSK3). GSK3 is a Pharmacological inhibition of GSK3 leads to the downregulation of pro-inflammatory cytokines and the upregulation of anti-inflammatory cytokines, mimicking the tolerance state. This result would suggest that GSK3 is active during the initial wave of LPS stimulation but becomes inactivated to prevent prolonged inflammation from occurring.
Evolution has equipped humans with an inflammatory response to help fight infection. However, this normally helpful response can have dire consequences when the body loses the ability to switch off the inflammatory signal and turn on the wound repair signal. Uncontrolled inflammation can result in long term, self-inflicted damage, much like auto-immune diseases. The brain is particularly sensitive where permanent neurological damage can occur. Understanding the molecular switches that can shift the balance towards wound healing may lead to strategies that will limit excessive inflammatory damage.