IL-1?, IL-6, and GM-CSF Are Downstream Mediators of IL-17A that Promote Asymmetric Stem Cell Self-Renewal in Human Keratinocytes

IL-17A, a key cytokine in the inflammation of psoriasis, is upregulated psoriatic skin and stimulates transcriptional activity correlating with psoriasis transcriptome (Chiricozzi et al., 2011Chiricozzi A. Guttman-Yassky E. Suárez-Fariñas M. Nograles K.E. Tian S. Cardinale I. al.Integrative responses to IL-17 TNF-? human keratinocytes account for inflammatory pathogenic circuits psoriasis.J Invest Dermatol. 2011; 131: 677-687Abstract Full Text PDF PubMed Scopus (404) Google Scholar). Asymmetric stem cell (SC) self-renewal (ASR) increased psoriasis. IL-17A increases ASR (KCs), divisions are IL-17A?dependent imiquimod-induced psoriasis-like mouse model (Charruyer 2017Charruyer Fong Vitcov G.G. Sklar Tabernik L. Taneja al.Brief report: interleukin-17A-dependent asymmetric psoriasis: mechanism underlying benign hyperproliferation.Stem Cells. 2017; 35: 2001-2007Crossref (9) Epidermal maintenance requires balance SC differentiation (Figure 1a). promote stratification by producing one basal (suprabasal) non-SC (a committed transit-amplifying progenitor) mice (Lechler Fuchs, 2005Lechler T. Fuchs mammalian skin.Nature. 2005; 437: 275-280Crossref (726) Scholar; Niessen 2013Niessen M.T. Scott J. Zielinski J.G. Vorhagen Sotiropoulou P.A. Blanpain C. al.aPKC? controls epidermal homeostasis fate through regulation division orientation.J Cell Biol. 2013; 202: 887-900Crossref (51) Williams 2011Williams S.E. Beronja Pasolli H.A. Notch-dependent differentiation.Nature. 470: 353-358Crossref (302) Scholar) humans Symmetric lead two SCs or differentiated progenitor cells. can be identified segregation fate-determinant proteins such as Numb 1b). We hypothesized that IL-17A?induced KC cytokines play role examined psoriasis-related produced KCs after treatment then determined their effects on ASR. production IL-1?, IL-6, IL-8, GM-CSF protein. Whereas there robust studies gene expression (e.g., Chiricozzi Scholar), this not case protein expression. IL-6 but results IL-1? IL-1? KCs, HaCaT cells, bronchial epithelial cells inconsistent (Albanesi 2000Albanesi Scarponi Cavani Federici Nasorri F. Girolomoni G. Interleukin-17 both Th1 Th2 lymphocytes, modulates interferon-gamma- interleukin-4-induced activation keratinocytes.J 2000; 115: 81-87Abstract (241) Laan 2001Laan Lötvall Chung K.F. Lindén IL-17-induced release vitro: mitogen-activated (MAP) kinases.Br J Pharmacol. 2001; 133: 200-206Crossref (167) Tan 2017Tan Q. Yang H. Liu E.M. Wang Establishing interleukin-17 atopic dermatitis-related inflammation.J Cutan Med Surg. 21: 308-315Crossref (19) Teunissen 1998Teunissen M.B. Koomen C.W. de Waal Malefyt R. Wierenga E.A. Bos J.D. interferon-? synergize enhancement proinflammatory 1998; 111: 645-649Abstract (470) investigated response ELISA. Neonatal samples were obtained written informed parental consent well approval from University California, San Francisco Committee Human Research. All abided rules Internal Review Board tenets Declaration Helsinki. significantly GM-CSF. The increase approached significance (P = 0.06) 1c). No significant difference was detected IL-1?, IL-2, IL-4, IL-10, IFN-?, TNF-?. IL-17A?treated previous studies, associated hyperproliferation (Takahashi 2009Takahashi Tsuji Hashimoto Y. Ishida-Yamamoto Iizuka proliferation induction tnf-? different normal vitro.Indian 2009; 54: 237-239Crossref (12) In may work indirect T helper type 17 myeloid dendritic explaining why did IL-8 divisions. Next, we analyzed effect GM-CSF, using immunofluorescence staining vitro. (51.2 ± 1.1%, 48.4 4.0%, 47.8 2.7%, respectively) IL-17A–treated versus vehicle-treated (37.3 0.8%, 36.4 3.8%, 34.2 1.0%, 1d e Supplementary Figure S1). observed correlated decreased symmetric no change treatment. antibodies reduce showed inhibited dose-dependent manner 2 antibody at ?0.1 ?g/ml, ?0.05 ?g/ml 2a–c S2a–c). most effective doses 77.3 8%, 54.3 24.3%, 59.3 11.8% ASR, respectively, resulting levels those e). tested whether an additive 2d S2d). GM-CSF+IL6, IL1?+IL6, GM-CSF+IL1? 76.7 6.2%, 57.7 24.9%, 65.4 19% divisions, respectively 2e). This because individual resulted KCs. It also possible missed untested mediators affect Cytokines found produce arise less more predominantly than other tissues. However, our show autocrine paracrine secretion Combination level vehicle, suggesting have some players concept divisional behavior evolving. murine hyperproliferative bowel disease (Bu 2016Bu P. Chen K.Y. Srinivasan Murthy P.K.L. Tung K.L. al.A miR-34a-numb feedforward loop triggered regulates intestine colon cancer.Cell Stem Cell. 2016; 18: 189-202Abstract (93) IL-22?treated intestinal (Zwarycz 2019Zwarycz B. Gracz A.D. Rivera K.R. Williamson I.A. Samsa L.A. Starmer al.IL22 inhibits expansion ileal organoid model.Cell Mol Gastroenterol Hepatol. 2019; 7: 1-17Abstract (32) Thus, mounting evidence regulate and/or specifically diseases. Notably, identified—IL-1a, GM-CSF—all activate NF-kB, transcription factor (Ebner 2003Ebner K. Bandion Binder B.R. Martin Schmid J.A. GMCSF activates NF-kappaB via direct interaction receptor IkappaB kinase beta.Blood. 2003; 102: 192-199Crossref (55) 2003Wang Walia Evans Gewirtz A.T. Merlin D. Sitaraman S.V. induces NF-kappa B epithelia.J Immunol. 171: 3194-3201Crossref (155) Perturbation NF-kB signaling various either hyperplasia hypoplasia (Lizzul 2005Lizzul P.F. Aphale Malaviya Sun Masud Dombrovskiy V. al.Differential phosphorylated NF-kappaB/RelA epidermis downregulation etanercept.J 124: 1275-1283Abstract (157) addition, required neural (Zhang 2012Zhang Yao Li Xin Lai al.Nuclear kappa initiates early cells.Stem 2012; 30: 510-524Crossref (74) Future will needed determine responsible stratification. mInsc LGN aPKC establish planar polarity during (Dainichi 2016Dainichi Hayden M.S. Park S.G. Oh Seeley J.J. Grinberg-Bleyer al.PDK1 regulator organizes division.Cell Rep. 15: 1615-1623Abstract (24) Genetic manipulations (mInsc overexpression) thicker (Williams (Lgn deletion knockout Pdk1) thinner Our suggests important evoked dissect molecular mechanisms identify new targets used combat cutaneous manifestations. Datasets related article https://doi.org/10.6084/m9.figshare.12241745, hosted Figshare Data repository. Hang Li: http://orcid.org/0000-0003-1843-8329 Alex Charruyer: http://orcid.org/0000-0003-4655-4781 Tracy Weisenberger: http://orcid.org/0000-0002-5849-2103 Ayman Khalifa: http://orcid.org/0000-0001-5828-0816 Robert Nguyen: http://orcid.org/0000-0002-6186-3243 Ruby Ghadially: http://orcid.org/0000-0002-2880-7987 authors state conflict interest. study supported Novartis Investigator-Initiated grant (Novartis Pharmaceuticals, AIN457AUSNCO2T) Merit Award Veterans Health Administration Office Research Development (BX000794). Conceptualization: HL, AC, RG; Curation: AC; Formal Analysis: RN, Funding Acquisition: Investigation: TW, AK, RN; Methodology: Project Administration: Resources: Supervision: Validation: Visualization: Writing - Original Draft Preparation: Editing: RG.