Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37.

Brain microglia cells are responsible for recognizing foreign bodies and act by activating other immune cells. Microglia react against infectious agents that cross the blood-brain barrier and release pro-inflammatory cytokines including interleukin (IL)-1β, IL-33 and tumor necrosis factor (TNF). Mast cells (MCs) are immune cells also found in the brain meninges, in the perivascular spaces where they create a protective barrier and release pro-inflammatory compounds, such as IL-1β, IL-33 and TNF. IL-1β binds to the IL-1R1 receptor and activates a cascade of events that leads to the production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activation of the immune system. IL-33 is a member of the IL-1 family expressed by several immune cells including microglia and MCs and is involved in innate and adaptive immunity. IL-33 is a pleiotropic cytokine which binds the receptor ST2 derived from TLR/IL-1R super family and is released after cellular damage (also called "alarmin"). These cytokines are responsible for a number of brain inflammatory disorders. Activated IL-1β in the brain stimulates microglia, MCs, and perivascular endothelial cells, mediating various inflammatory brain diseases. IL-37 also belongs to the IL-1 family and has the capacity to suppress IL-1β with an anti-inflammatory property. IL-37 deficiency could activate and enhance myeloid differentiation (MyD88) and p38-dependent protein-activated mitogenic kinase (MAPK) with an increase in IL-1β and IL-33 exacerbating neurological pathologies. In this article we report for the first time that microglia communicate and collaborate with MCs to produce pro-inflammatory cytokines that can be suppressed by IL-37 having a therapeutic potentiality.