Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit - PubMed (original) (raw)

Figure 1

The paradigm of the CNS neuroinflammation. Various factors can activate the immune response of the CNS and induce neuroinflammation. These stimuli are classified into two groups: 1—pathogen-associated molecular patterns (PAMPs), which are produced by the invading microorganisms of the CNS and 2—damage-associated molecular patterns (DAMPs), molecules that are released by host due to onset of traumatic conditions or interaction with some neurotransmitters (i.e., glutamate, GABA, and acetylcholine). The immune responses to the CNS stimuli vary based on the type of stimulation but generally lead to similar outcomes such as immune adaptation, dysfunction, degeneration, and resolution. Activation of the resting microglia and converting them to two distinct phenotypes depends on various cytokines produced by surrounding cells (glia, neurons, migratory immune cells). The release of interleukins 4 and 13 (IL-4, IL-13) gives rise to M1 phenotype (anti-inflammatory) of microglia, which express inflammatory cytokines (interleukin 4, 10, and 13), cell growth factors (i.e., NGF, BDNF, TGF-β, GDNF), and exert anti-inflammatory effects. Interferon-γ (IFN-γ) and the lipopolysaccharide (LPS) of bacteria, on the other hand, activate the M2 phenotype (pro-inflammatory) of microglia. The M2 phenotype is characterized by 1—activation of purinergic receptors P2X7 subtype (activated by ATP, promoting the inflammation and destruction of cells by forming channels and pores), and 2—expression of enzymes which generate reactive oxygen and nitrogen [NAD(P)H-oxidase, iNOS], and trigger the expression of proinflammatory cytokines (IL-1β, TNF-α, IL-6, IFN- γ). Activation of microglia, especially the formation of M2 phenotype exacerbates the damage to BBB (in particular neurons and endothelial cells). Effects of these agents (PAMPs, DAMPs, neuromediators) on astroglia cause their proliferation, activation (reactive astrogliosis), and dysfunction (in particular, increased procoagulant activity and thrombosis). These CNS stimuli also cause endothelial injury, damage, and neuronal death. GABA, γ-aminobutyric acid; IL, Interleukin; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; TGF, transforming growth factor; GDNF, glial-derived neurotrophic factors; iNOS, inducible nitric oxide synthase; TNF, tumor necrosis factor; IFN, interferon; ROS, reactive oxygen species; NO, nitric oxide.