Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells

Caspase-8 deficiency in the epidermis (caspase-8EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation of Il-33 or St2 dramatically delays lesion development and improves survival of caspase-8EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation. Teaser Inhibition of IL-33/ST2 axis alleviates necroptosis-induced skin inflammation by reducing TNF production in the dermis.

[1]  J. Girard,et al.  Interleukin-33 (IL-33): A critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine. , 2022, Cytokine.

[2]  H. Turnquist,et al.  Emerging Functions of IL-33 in Homeostasis and Immunity. , 2022, Annual review of immunology.

[3]  I. Dikic,et al.  OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice , 2021, Nature Communications.

[4]  Y. Saeys,et al.  OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity , 2021, Nature Communications.

[5]  K. Bogunia-Kubik,et al.  IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients , 2021, Frontiers in Immunology.

[6]  U. Klein,et al.  NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation , 2021, Life Science Alliance.

[7]  P. Vandenabeele,et al.  Mouse Strain-Dependent Difference Toward the Staphylococcus aureus Allergen Serine Protease-Like Protein D Reveals a Novel Regulator of IL-33 , 2020, Frontiers in Immunology.

[8]  Jun Li,et al.  An Autocrine Circuit of IL-33 in Keratinocytes is Involved in the Progression of Psoriasis. , 2020, The Journal of investigative dermatology.

[9]  Y. Imai,et al.  Interleukin-33 in atopic dermatitis. , 2019, Journal of dermatological science.

[10]  S. Cullen,et al.  RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity. , 2019, Cell Reports.

[11]  Tetsuro Kobayashi,et al.  Choreographing Immunity in the Skin Epithelial Barrier , 2019, Immunity.

[12]  B. Croker,et al.  Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model , 2019, The FEBS journal.

[13]  Junying Yuan,et al.  Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression , 2018, Cell Death & Disease.

[14]  Junying Yuan,et al.  Necroptosis in development and diseases , 2018, Genes & development.

[15]  J. Girard,et al.  Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family , 2018, Immunological reviews.

[16]  M. Pasparakis,et al.  RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation , 2016, Nature.

[17]  B. Monsarrat,et al.  Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells , 2016, Scientific Reports.

[18]  M. Gaestel,et al.  MK2/3 Are Pivotal for IL-33–Induced and Mast Cell–Dependent Leukocyte Recruitment and the Resulting Skin Inflammation , 2016, The Journal of Immunology.

[19]  Y. Tada,et al.  Serum IL‐33 levels are increased in patients with psoriasis , 2016, Clinical and experimental dermatology.

[20]  Michael U. Martin,et al.  Interleukin 33 is a guardian of barriers and a local alarmin , 2016, Nature Immunology.

[21]  W. Shi,et al.  The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells , 2015, Nature Immunology.

[22]  M. Pasparakis,et al.  RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis , 2014, Nature.

[23]  L. Eckhart,et al.  Cell death by cornification. , 2013, Biochimica et biophysica acta.

[24]  G. Nilsson,et al.  Intraperitoneal influx of neutrophils in response to IL-33 is mast cell-dependent. , 2013, Blood.

[25]  A. McKenzie,et al.  IL-33 citrine reporter mice reveal the temporal and spatial expression of IL-33 during allergic lung inflammation , 2012, European journal of immunology.

[26]  M. Ermolaeva,et al.  The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. , 2011, Immunity.

[27]  Ashley M. Miller,et al.  IL‐33 induces skin inflammation with mast cell and neutrophil activation , 2011, European journal of immunology.

[28]  T. Kang,et al.  Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease , 2009, The Journal of experimental medicine.

[29]  Irene L. Ch’en,et al.  Dynamic expression of epidermal caspase-8 simulates a wound healing response , 2009, Nature.

[30]  P. Chambon,et al.  Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. , 2006, Human molecular genetics.

[31]  Daniel R. Beisner,et al.  Cutting Edge: Innate Immunity Conferred by B Cells Is Regulated by Caspase-81 , 2005, The Journal of Immunology.

[32]  Werner Müller,et al.  Keratin 14 Cre transgenic mice authenticate keratin 14 as an oocyte‐expressed protein , 2004, Genesis.

[33]  E. S. Baekkevold,et al.  Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. , 2003, The American journal of pathology.

[34]  T. Rülicke,et al.  T1‐deficient and T1‐Fc‐transgenic mice develop a normal protective Th2‐type immune response following infection with Nippostrongylus brasiliensis , 2000, European journal of immunology.

[35]  P. Matzinger.  Tolerance, danger, and the extended family. , 1994, Annual review of immunology.