TY - JOUR
T1 - Contribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis
AU - Oulès, Bénédicte
AU - Philippeos, Christina
AU - Segal, Joe
AU - Tihy, Matthieu
AU - Vietri Rudan, Matteo
AU - Cujba, Ana-Maria
AU - Grange, Philippe A
AU - Quist, Sven
AU - Natsuga, Ken
AU - Deschamps, Lydia
AU - Dupin, Nicolas
AU - Donati, Giacomo
AU - Watt, Fiona M
N1 - Funding Information:
We are grateful to all members of the Watt laboratory for helpful discussions. We thank Simon Broad and Ajay Mishra for constant help and advice; Rocio Sancho for helping with organoid protocols; Arsham Ghahramani for helping with computational analysis; and Mark Soldin for providing skin samples. We thank Anne Couvelard, Karim Tabbech and Amina El Hilali from the Pathology Department of Hôpital Bichat (AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, France) for histopathological analyses. We are grateful for funding from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. We are grateful to the BRC Flow Cytometry Facility, King’s College Hospital/ NHS Foundation Trust and to the Nikon Imaging Centre, King’s College London, for technical support. This work was funded by grants to F.M.W. from the UK Medical Research Council (G1100073), the Wellcome Trust (096540/Z/11/Z) and from Unilever.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.
AB - Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.
UR - http://www.scopus.com/inward/record.url?scp=85093086553&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-18784-z
DO - 10.1038/s41467-020-18784-z
M3 - Article
C2 - 33082341
SN - 2041-1723
VL - 11
SP - 5067
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5067
ER -
