To ‘feel comfortable in one’s own skin’ is an idiom referring to one’s confidence in interacting with others. However, when the skin is inflamed, as in atopic dermatitis or psoriasis, patients carry a sub-stantial burden leading to opposite effects. Current therapies target redundant, late-stage inflammatory events but not the disease drivers, leading to heterogeneous and insufficient efficacy. Understanding the proximal mechanisms of inflammation will stimulate the development of better therapies. Among the innate immune sensors for stress and microbes in keratinocytes, mutations in the NLRP1 and NLRP10 inflammasomes are linked to skin disorders. These molecules and the pro- and anti-inflammatory IL-1 family members they regulate are differentially expressed in the different layers of the epidermis. We hypothesize that inflammasome signaling in keratinocytes needs context-dependent and spatio-temporal control to avoid inflammation, which poses unique analytical and conceptual challenges. Therefore, to understand how inflammasome signaling in specific keratinocytes drives skin inflammation, 4D-SkINFLAM will i. optogenetically activate specific inflammasome components with spatio-temporal precision and perform a spatial analysis of transcriptomes and proteomes in neighboring cells. With loss-of-function approaches and pathway activity reporters, we will ii. define the ‘sensome’ and the activity of inflammasomes in different areas of the epidermis. Using mouse models, we will iii. evaluate how spatial inflammasome activity drives skin inflammation. Through iv. AI-driven deep visual proteomics combined with an analysis of inflammasome activity, we will discover spatial in-flammasome activation and its effects in inflammatory skin disorders. A precise understanding of spatio-temporal inflammasome signaling in the skin will be critical for se-lecting therapeutic targets acting as upstream drivers of prevalent diseases with high unmet needs.