Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

Area of Science:

• Cellular Biology
• Dermatology
• Stem Cell Biology

Background:

• Macroautophagy/autophagy is a fundamental cellular process involved in cell survival and inflammatory response regulation.
• Autophagy's role in skin homeostasis and the specific functions of autophagy mediators like ATG16L1 in keratinocytes are not fully understood.
• Keratinocyte stem cell activation is critical for skin repair and hair follicle development.

Purpose of the Study:

• To investigate the role of keratinocyte autophagy, specifically mediated by ATG16L1, in regulating skin inflammation, neoplastic responses, and hair follicle stem cell (HFSC) activation.
• To elucidate the mechanisms by which autophagy deficiency impacts HFSC behavior and sensitivity to cell death pathways.

Main Methods:

• Generated keratinocyte-selective Atg16l1 knockout mice to study the effects of autophagy ablation.
• Assessed inflammatory and neoplastic skin responses, hair follicle development, and HFSC activation kinetics.
• Utilized genetic deletion of apoptosis (CASP8) and necroptosis (RIPK3) pathways, and TNFR1 signaling to investigate cell death sensitivity.
• Analyzed HFSC potency through de novo hair follicle formation and wound healing assays.

Main Results:

• Ablation of Atg16l1 in keratinocytes led to heightened inflammatory and neoplastic skin responses.
• Autophagy-deficient mice showed precocious hair follicle growth and expanded HFSC potencies, including de novo follicle formation and enhanced wound healing.
• ATG16L1-deficient keratinocytes exhibited increased sensitivity to TNF-dependent apoptosis and necroptosis, which was identified as the driver for altered HFSC activation.

Conclusions:

• Keratinocyte autophagy acts as a crucial brake on skin inflammation and tumorigenesis.
• Autophagy restrains HFSC activation by modulating apoptotic responses, thereby limiting their proliferative potential.
• Targeting keratinocyte autophagy could offer therapeutic strategies for inflammatory skin diseases and cancer, while also influencing regenerative processes.