Induction of IL-33 expression and activity in central nervous system glia

Abstract

IL-33 is a novel member of the IL-1 cytokine family and a potent inducer of type 2 immunity, as mast cells and Th2 CD4+ T cells respond to IL-33 with the induction of type 2 cytokines such as IL-13. IL-33 mRNA levels are extremely high in the CNS, and CNS glia possess both subunits of the IL-33R, yet whether IL-33 is produced by and affects CNS glia has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase IL-33 mRNA and protein expression in CNS glia. Interestingly, IL-33 was localized to the nucleus of astrocytes. Further, CNS glial and astrocyte-enriched cultures treated with a PAMP followed by an ATP pulse had significantly higher levels of supernatant IL-1beta and IL-33 than cultures receiving any single treatment (PAMP or ATP). Supernatants from PAMP + ATP-treated glia induced the secretion of IL-6, IL-13, and MCP-1 from the MC/9 mast cell line in a manner similar to exogenous recombinant IL-33. Further, IL-33 levels and activity were increased in the brains of mice infected with the neurotropic virus Theiler's murine encephalomyelitis virus. IL-33 also had direct effects on CNS glia, as IL-33 induced various innate immune effectors in CNS glia, and this induction was greatly amplified by IL-33-stimulated mast cells. In conclusion, these results implicate IL-33-producing astrocytes as a potentially critical regulator of innate immune responses in the CNS.

P2 receptor-mediated signaling in mast cell biology

“…IL-33 acts via the ST1 receptor which is highly expressed on mast cells and induces release of TNFα, IL-1β, IL-6, IL-13, RANTES, GM-CSF, MCP-1, MIP1α, and MIP1β by BMMCs [90]. Supernatants from ATP and PAMPs-treated glial cells induced secretion of IL-6, IL-13, and MCP-1 by MC/9 cells similar to the effect of the recombinant IL-33 [110]. These pro-inflammatory cytokines could stimulate the glial cells in return.…”

“…4) TNFα release from glial cells [49,51,52]. Treatment of cells with PAMPs (dsRNA or LPS) that was followed by ATP pulse significantly induced the release of IL-1β and IL-33 by the glial cells [110]. IL-33 acts via the ST1 receptor which is highly expressed on mast cells and induces release of TNFα, IL-1β, IL-6, IL-13, RANTES, GM-CSF, MCP-1, MIP1α, and MIP1β by BMMCs [90].…”

“…As was noted above, ATP mediates release of IL-33 from glial cells. While IL-33 governs Th2 immune response, it also mediates secretion of IL-13 by mast cells [90,110], which could further amplify the Th2-mediated response. Therefore, purine/cytokine-mediated crosscommunication between mast-nerve-glial cells represents a key neural-immune interaction in CNS inflammation and autoimmune diseases.…”

The enigmatic processing and secretion of interleukin-33

“…60 Also, over 1 ng/ml of IL-33 has been detected in the supernatants of cultured astrocytes stimulated by lipopolysaccharide and adenosine triphosphate. 61 Such apparently contradictory results should be considered as an indication that processing and secretion of IL-33 is an extremely complex process. Further efforts are needed to reach a conclusion, though addressing the following issues should help clarify the situation.…”

“…IL-33 is reported to be constitutively expressed by endothelial, 1,2,62,63 epithelial 63 and smooth muscle cells. 2,34 Additionally, inducible expression of IL-33 has been described in activated macrophage, 2,46 fibroblasts and keratinocytes exposed to tumour-necrosis factor-a and IL-1b, 2 astrocytes stimulated by lipopolysaccharide and adenosine triphosphate, 61 and adipocytes activated by tumour-necrosis factora. 64 IL-33 is also induced when cultured endothelial cells reach confluence and stop proliferating.…”