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

Lisette Van Hove; Annagiada Toniolo; Mohammad Ghiasloo; Kim Lecomte; Fleur Boone; Maarten Ciers; Kris Raaijmakers; Niels Vandamme; Jana Roels; Sophia Maschalidi; Kodi S Ravichandran; Maria Kasper; Geert van Loo; Esther Hoste

doi:10.1080/15548627.2023.2247742

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

Autophagy. 2023 Nov;19(11):2958-2971. doi: 10.1080/15548627.2023.2247742. Epub 2023 Sep 1.

Authors

Lisette Van Hove^{1

2

3}, Annagiada Toniolo^{1

2

3}, Mohammad Ghiasloo^{1

2

4}, Kim Lecomte^{1

2

3}, Fleur Boone^{1

2

3}, Maarten Ciers^{1

2

3}, Kris Raaijmakers^{1

2

3}, Niels Vandamme^{1

5}, Jana Roels^{1

5}, Sophia Maschalidi^{1

2}, Kodi S Ravichandran^{1

2}, Maria Kasper⁶, Geert van Loo^{1

2

3}, Esther Hoste^{1

2

3}

Affiliations

¹ VIB Center for Inflammation Research, Ghent, Belgium.
² Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
³ Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
⁴ Department of Plastic and Reconstructive Surgery, Ghent University Hospital, Ghent, Belgium.
⁵ VIB Single Cell Core, Ghent-Leuven, Belgium.
⁶ Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Abstract

Macroautophagy/autophagy is a cellular recycling program regulating cell survival and controlling inflammatory responses in a context-dependent manner. Here, we demonstrate that keratinocyte-selective ablation of Atg16l1, an essential autophagy mediator, results in exacerbated inflammatory and neoplastic skin responses. In addition, mice lacking keratinocyte autophagy exhibit precocious onset of hair follicle growth, indicating altered activation kinetics of hair follicle stem cells (HFSCs). These HFSCs also exhibit expanded potencies in an autophagy-deficient context as shown by de novo hair follicle formation and improved healing of abrasion wounds. ATG16L1-deficient keratinocytes are markedly sensitized to apoptosis. Compound deletion of RIPK3-dependent necroptotic and CASP8-dependent apoptotic responses or of TNFRSF1A/TNFR1 reveals that the enhanced sensitivity of autophagy-deficient keratinocytes to TNF-dependent cell death is driving altered activation of HFSCs. Together, our data demonstrate that keratinocyte autophagy dampens skin inflammation and tumorigenesis but curtails HFSC activation by restraining apoptotic responses.Abbreviations: ATG16L1: autophagy related 16 like 1; DMBA: 2,4-dimethoxybenzaldehyde; DP: dermal papilla; EpdSCs: epidermal stem cells; Gas6: growth arrest specific 6; HF: hair follicle; HFSC: hair follicle stem cell; IFE: interfollicular epidermis; KRT5: keratin 5; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PMK: primary mouse keratinocyte; RIPK3: receptor-interacting serine-threonine kinase 3; scRNAseq: single-cell RNA-sequencing; SG: sebaceous gland; TEWL: transepidermal water loss; TPA: 12-O-tetradecanoylphorbol-13-acetate; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a; UMAP: uniform manifold approximation and projection.

Keywords: Apoptosis; autophagy; hair cycling; hair follicle stem cells; skin cancer; wound healing.

Grants and funding

The work was supported by the Fonds Wetenschappelijk Onderzoek [11ZZQ20N]; Fonds Wetenschappelijk Onderzoek [1S57322N]; Fonds Wetenschappelijk Onderzoek [11ZZQ20N, 1S57322N,12A0319N]; LEO Fondet [Leo Foundation Award EMEA 2022]; Stichting Tegen Kanker [F/2022/1899].L.v.H. received an FWO fellowship to perform this work (11ZZQ20N). M.G. is the funded by an FWO SB fellowship (1S57322N). E.H. is the recipient of the Leo Foundation Award EMEA 2022 and an FWO postdoctoral fellowship (12A0319N). This work was funded by an FWO Research grant (1500319N) and by Foundation against cancer (F/2022/1899). Maria Kasper: M.K. was supported by a Swedish Research Council grant 2022-01059 and a Swedish Cancer Society grant 21 1821 Pj. We thank the EUCOMM consortium for Atg16L1-targeted ES cells, Vishva Dixit and Genentech for providing the RIPK3-/- mice, and Laetitia Bellen, Dimitri Huygebaert and Dieter Vanhede for animal care. We acknowledge technical assistance from the VIB Single Cell Core facility, VIB Flowcore, VIB Bioimaging Core and VIB Nucleomics Core.