Interleukin-36 (IL-36) is the common name for the three IL-1 family members IL-36α, IL-36β and IL-36γ, formerly known as IL-1F6, IL-1F8 and IL-1F9, respectively. IL-36 appears to have pro-inflammatory activities; however, the physiological function of these cytokines remains unknown. Expression of IL-36 by keratinocytes implies its possible involvement in innate immune responses in the skin. We observed that, of the three IL-36 isoforms, human keratinocytes express high levels of IL-36γ. IL-36γ mRNA expression was dramatically induced by the Toll-like receptor ligands poly(I:C) and flagellin. Surprisingly, the IL-36γ protein was released by cells treated with poly(I:C) but remained intracellular in cells treated with flagellin only. Poly(I:C), but not flagellin, induced cell death and caspase-3/7 activation. Inhibition of caspase-3/7 and caspase-1 blocked extracellular release of IL-36γ from poly(I:C) treated cells. Furthermore, caspase-1 inhibition prevented poly(I:C)-induced caspase-3/7 activation. Interestingly, transcription of the gene IL36G was dependent upon caspase-1, but not caspase-3/7, activation. This demonstrates that the pathways leading to IL36G transcription and caspase-3/7 activation branch after caspase-1. This divergence of the pathways allows the cells to enter a state of de novo protein synthesis before committing to pyroptosis. Overall our observations suggest that IL-36γ may be an alarmin that signals the cause, e.g. viral infection, of cell death.

Munro’s microabscesses contain polymorphonuclear leukocytes and form specifically in the epidermis of psoriasis patients. The mechanism whereby the neutrophils are recruited into the epidermis is poorly understood. Using a combination of human and mouse primary keratinocyte cell cultures and the imiquimod-induced psoriasis-like mouse model of skin inflammation we explored the role of interleukin-1 (IL-1) signaling in microabscess formation. In vitro imiquimod stimulated production of IL-1α and neutrophil recruiting chemokines. Imiquimod activated chemokine expression was dependent upon adenosine signaling and independent of IL-1α and IL-1 receptor type 1 (IL-1R1); nevertheless, IL-1α could enhance chemokine expression initiated by imiquimod. Topical application of imiquimod in vivo led to epidermal microabscess formation, acanthosis and increased IL-1α and chemokine expression in the skin of wild type mice. However, in IL-1R1 deficient mice these responses were either absent or dramatically reduced. These results demonstrate that IL-1α and IL-1R1 signaling is essential for microabscess formation, neutrophil recruiting chemokine expression and acanthosis in psoriasis-like skin inflammation induced by imiquimod.

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Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.

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