Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

Area of Science:

• Immunology
• Stem Cell Biology
• Dermatology

Background:

• The skin barrier, crucial for defense, is maintained by epithelial stem cells (EpSCs).
• The response of EpSCs to inflammation and its long-term effects are not fully understood.
• EpSCs are vulnerable to inflammatory damage.

Purpose of the Study:

• To investigate the enduring consequences of acute inflammation on mouse epithelial stem cells (EpSCs).
• To identify the mechanisms by which EpSCs adapt to and 'remember' inflammatory events.
• To understand how this stem cell memory influences skin barrier repair.

Main Methods:

• Acute inflammation model in mice.
• Analysis of EpSC function and gene expression post-inflammation.
• Genetic manipulation involving Aim2, caspase-1, and interleukin-1β.

Main Results:

• Mouse EpSCs exhibit a prolonged memory of acute inflammation, accelerating barrier restoration after secondary damage.
• This functional adaptation in EpSCs is independent of skin-resident macrophages and T cells.
• EpSCs maintain chromosomal accessibility at stress-response genes, enabling rapid transcription upon re-exposure to inflammation, mediated by Aim2 inflammasome signaling.
• Loss of Aim2, caspase-1, or interleukin-1β abrogates this inflammatory memory in EpSCs.

Conclusions:

• Epithelial stem cells possess an intrinsic memory of inflammation, enhancing tissue repair.
• Aim2 inflammasome pathway is critical for establishing and maintaining this EpSC inflammatory memory.
• While beneficial for repair, enhanced EpSC sensitivity due to inflammation may increase susceptibility to autoimmune diseases and cancer.