Spatio-temporal integration of skin inflammation

Introduction

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 substantial 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.

Background

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.

Objectives

Therefore, to understand how inflammasome signaling in specific keratinocytes drives skin inflammation, 4D-SkINFLAM will:

1. Optogenetically activate specific inflammasome components with spatio-temporal precision and perform a spatial analysis of transcriptomes and proteomes in neighboring cells.
2. Define the ‘sensome’ and the activity of inflammasomes in different areas of the epidermis using loss-of-function approaches and pathway activity reporters.
3. Evaluate how spatial inflammasome activity drives skin inflammation using mouse models.
4. Discover spatial inflammasome activation and its effects in inflammatory skin disorders through AI-driven deep visual proteomics combined with an analysis of inflammasome activity.

Conclusion

A precise understanding of spatio-temporal inflammasome signaling in the skin will be critical for selecting therapeutic targets acting as upstream drivers of prevalent diseases with high unmet needs.