Neuroinflammation Signaling Pathway

Neuroinflammatory signaling plays a key role in maintaining the homeostasis of central nervous system (CNS), functioning to destroy and remove damaging agents and clear injured neural tissues. When this beneficial inflammatory response is uncontrolled, excessive cell and tissue damage can ensue that results in destruction of normal tissue and chronic inflammation that ultimately results in necrosis of glial cells and neurons. Chronic neuroinflammation is closely associated with chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis and has also been a focus of research into the pathology underlying psychiatric disorders like depression.At the early stage of inflammation, self-limiting mechanisms, such as apoptotic destruction of activated glial cells and injured neurons keeps a balance between brain tissue protection and damage, but when compromised, the inflammatory processes can be accelerated by neurons which turn on the expression of multiple pro-inflammatory cytokines, neurotransmitters or modulators (glutamate, fractalkine, nitric oxide, GABA) and neurotoxic proteins (amyloid beta peptide (A-beta), heat-shock proteins, HMGB1). These signals, also termed as damage associated molecular pattern (DAMP) molecules, recruit microglia and enhance their activities, which exacerbates neuronal damage.Activated microglia have key roles in neuroinflammation, and depending on the nature of the initial stimulus their actions may be either beneficial or detrimental to neuronal function. Microglial response to CNS pathology also results in initiation of a number of immune functions including phagocytosis and production of both cytotoxic and neurotrophic mediators. Short-term microglial activity is generally thought to serve a neuroprotective role, which has been shown to occur due to exposure to IL-4 and low levels of IFN cytokines.In chronic neurodegenerative diseases, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual. Astrocytes have also been implicated in the production of cytotoxic mediators, including reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines and chemokines which increase neuronal vulnerability. Oxidative stress generated by reactive glial cells is though to be the most critical factor in inducing the death of neuronal populations.Released cytokines promote the leakage of brain-blood barrier (BBB), resulting in the recruitment of immune cells from the blood circulation into the CNS parenchyma. Another important function of microglia is the presentation of foreign antigens to T lymphocytes. Astrocytes also express low levels of MHC therefore are capable of processing and presenting myelin protein epitopes to T cells.Furthermore, neurons, microglia, and astrocytes have been shown to up-regulate Fas ligand under inflammatory conditions, which can induce apoptosis through the FasL/Fas pathway. FasL/Fas system should be considered as a double-edged sword in the CNS, because in normal brain maintains the immune suppressed status but in the case of a variety of neurodegenerative disorders induces dysregulated neuronal cell death and inflammation.