Our aim was to revisit the primary sterile epidermis lesion considering the alarmins constitutively expressed in the skin tissue and notably the IL-1 family members (IL-1fm) released by lesional keratinocytes.
We profiled human keratinocyte IL1fm both at mRNA and protein level and modelized epidermis lesion using a standardized keratinocyte lysate or recombinant IL-1fm in stimulation assays in a panel of skin resident cells or leukocytes. IL-8 and IL-6 were used as consensus chemokine and pro-inflammatory cytokine read-out, respectively.
Keratinocytes expressed at mRNA level IL1fm agonists (IL1A, IL1B, IL18, IL33, IL36G) and antagonists (IL1RN, IL18BP, IL36RN). Cells in culture spontaneously released low and significant amounts of IL-36g and IL-1Ra, respectively. Quantifications of IL1fm intracellular content showed for IL-36 and IL-18 twice the amount of IL-1α. IL-1β was also detected whereas IL-33 was not. Among antagonists, IL-36Ra was detected, but the most striking point was the huge amounts of IL-1Ra in the lysate (over 100-fold than IL-1). Among all tested cell types (melanocytes, endothelial cells, leukocytes and keratinocytes themselves), fibroblasts exhibited by far the strongest sensitivity to keratinocyte lysate. Stimulations of fibroblasts with IL-1fm evidenced IL-1α(β) as the most active cytokines, already efficient at picomolar concentrations. A 4-log difference in IL-1 active doses was shown between fibroblasts and keratinocytes. In addition, the effect of keratinocyte lysate on fibroblasts was completely blocked by anti-IL-1 receptor Ab and the effects of keratinocyte lysate and IL-1α on fibroblast gene expression profile completely overlapped. Finally, we showed in titration experiments that fibroblasts stimulated by IL-1α remained insensitive to IL-1Ra, even in 100-fold excess.
Altogether these data indicate that fibroblasts may act as local sensors of primary epidermis lesion through keratinocyte IL-1 release. In this context, IL1-Ra released together with IL-1, should protect other skin cells from activation and limit the inflammatory response.

Fibroblasts are potentially the key sensors of epidermis lesion through keratinocyte IL-1 signalling