Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

  • Nature volume 550, pages 475480 (26 October 2017)
  • doi:10.1038/nature24271
  • Download Citation


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.

  • Subscribe to Nature for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


Primary accessions

Gene Expression Omnibus


  1. 1.

    & Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science 344, 1242281 (2014)

  2. 2.

    & Lineage analysis of epidermal stem cells. Cold Spring Harb. Perspect. Med. 4, a015206 (2014)

  3. 3.

    et al. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521, 366–370 (2015)

  4. 4.

    , & Emerging interactions between skin stem cells and their niches. Nat. Med. 20, 847–856 (2014)

  5. 5.

    et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006)

  6. 6.

    et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009)

  7. 7.

    & TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138–3146 (2013)

  8. 8.

    , , & The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999)

  9. 9.

    et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl Acad. Sci. USA 103, 11736–11741 (2006)

  10. 10.

    , , & Peripheral inflammation is associated with remote global gene expression changes in the brain. J. Neuroinflammation 11, 73 (2014)

  11. 11.

    , , , & Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 21, 1358–1366 (2007)

  12. 12.

    et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015)

  13. 13.

    et al. Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin. Cell 167, 1323–1338 (2016)

  14. 14.

    et al. Murine model of wound healing. J. Vis. Exp. 75, 50265 (2013)

  15. 15.

    et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012)

  16. 16.

    Resident memory T cells in human health and disease. Sci. Transl Med. 7, 269rv1 (2015)

  17. 17.

    et al. Trained immunity: A program of innate immune memory in health and disease. Science 352, aaf1098 (2016)

  18. 18.

    , , & ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9 (2015)

  19. 19.

    , , , & Identifying ChIP-seq enrichment using MACS. Nat. Protocols 7, 1728–1740 (2012)

  20. 20.

    et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010)

  21. 21.

    et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010)

  22. 22.

    , , & Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos. Nat. Med. 16, 821–827 (2010)

  23. 23.

    et al. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15, 453–457 (1997)

  24. 24.

    , & AIM2 inflammasome in infection, cancer, and autoimmunity: role in DNA sensing, inflammation, and innate immunity. Eur. J. Immunol. 46, 269–280 (2016)

  25. 25.

    et al. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci. Transl Med. 3, 82ra38 (2011)

  26. 26.

    et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162, 45–58 (2015)

  27. 27.

    et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat. Med. 21, 906–913 (2015)

  28. 28.

    et al. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354, 765–768 (2016)

  29. 29.

    et al. The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities. Sci. Rep. 6, 24166 (2016)

  30. 30.

    et al. Stem cell lineage infidelity drives wound repair and cancer. Cell 169, 636–650.e14 (2017)

  31. 31.

    et al. Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 167, 187–202.e17 (2016)

  32. 32.

    et al. Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma. Oncotarget 8, 45825–45836 (2017)

  33. 33.

    et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005)

  34. 34.

    et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008)

  35. 35.

    et al. Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma. Proc. Natl Acad. Sci. USA 111, 255–260 (2014)

  36. 36.

    , & Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127, 171–183 (2006)

  37. 37.

    et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

  38. 38.

    et al. Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J. Neurosci. 20, 4398–4404 (2000)

  39. 39.

    & Isolation and culture of epithelial stem cells. Methods Mol. Biol. 482, 215–232 (2009)

  40. 40.

    & Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature 265, 421–424 (1977)

  41. 41.

    . et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013)

  42. 42.

    , & Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014)

  43. 43.

    , , , & Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013)

  44. 44.

    , , & CEAS: cis-regulatory element annotation system. Bioinformatics 25, 2605–2606 (2009)

  45. 45.

    et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

  46. 46.

    , , & Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

  47. 47.

    et al. The UCSC Genome Browser database: 2016 update. Nucleic Acids Res. 44, D717–D725 (2016)

Download references


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.).

Author information

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


  1. Search for Shruti Naik in:

  2. Search for Samantha B. Larsen in:

  3. Search for Nicholas C. Gomez in:

  4. Search for Kirill Alaverdyan in:

  5. Search for Ataman Sendoel in:

  6. Search for Shaopeng Yuan in:

  7. Search for Lisa Polak in:

  8. Search for Anita Kulukian in:

  9. Search for Sophia Chai in:

  10. Search for Elaine Fuchs in:


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.

Extended data

Supplementary information


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.