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Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

Nature volume 550, pages 475480 (26 October 2017) | Download Citation

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The skin barrier is the body’s first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.

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  • 04 July 2018

    In Fig. 2g of this Article, the 'D30 IMQ' image was inadvertently presented as a duplicate of the 'D6 Ctrl' image. The old, incorrect Fig. 2g is shown in the Supplementary Information to the accompanying Amendment. The original Article has been corrected (note scale bar of new panel).


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We thank M. Nikolova, E. Wong and J. Levorse for technical assistance, and Y. Miao, I. Matos, Y. Ge, B. Keyes and R. Yi for discussions. FACS was conducted by Rockefeller’s Flow Cytometry Core (S. Mazel, director); ATAC-seq and RNA-seq were conducted by Rockefeller’s Genomics Core and Weill Cornell Genomics Center, respectively. E.F. is an Investigator of the Howard Hughes Medical Institute. S.N. is a Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2183-14) and L’Oreal USA For Women in Science. S.B.L. is funded by a National Institutes of Health (NIH) Ruth L. Kirschstein Predoctoral Fellowship (F31-AR068920-01A1). A.S. is funded by People Programme Marie Curie Actions (no. 629861). This study was supported by grants from the Robertson Foundation (S.N.), National Psoriasis Foundation (CEN5402062, S.N.), Pfizer (WI206828, S.N.) and NIH (R01-AR31737 and R01-AR050452, E.F.).

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Author notes

    • Shruti Naik
    •  & Samantha B. Larsen

    These authors contributed equally to this work.


  1. Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA

    • Shruti Naik
    • , Samantha B. Larsen
    • , Nicholas C. Gomez
    • , Kirill Alaverdyan
    • , Ataman Sendoel
    • , Shaopeng Yuan
    • , Lisa Polak
    • , Anita Kulukian
    • , Sophia Chai
    •  & Elaine Fuchs


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S.N., S.B.L. and E.F. conceptualized the study, designed experiments and wrote the manuscript. S.N. and S.B.L. performed all animal, flow cytometry, microscopy, and genomic experiments. N.C.G. and A.S. analysed the ATAC–seq and RNA-seq datasets. K.A. performed qPCR validations, cell culture experiments and cloned the TRE-Aim2 overexpression construct. S.Y. assisted with culture studies and statistical analysis for wound healing studies. L.P. performed abrasion wound studies. A.K. helped to design the TRE-Aim2 overexpression construct. S.C. engineered the Krt10-creER mice.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Shruti Naik or Elaine Fuchs.

Reviewer Information Nature thanks R. Flavell, X. Dai and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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