title: RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3-dependent control of STAT1.
abstract: Crosstalk between keratinocytes and immune cells is crucial for the immunological barrier function of the skin, and aberrant crosstalk contributes to inflammatory skin diseases. Using mice with a keratinocyte-restricted deletion of the RAC1 gene we found that RAC1 in keratinocytes plays an important role in modulating the interferon (IFN) response in skin. These RAC1 mutant mice showed increased sensitivity in an irritant contact dermatitis model, abnormal keratinocyte differentiation, and increased expression of immune response genes including the IFN signal transducer STAT1. Loss of RAC1 in keratinocytes decreased actin polymerization in vivo and in vitro and caused Arp2/3-dependent expression of STAT1, increased interferon sensitivity and upregulation of aberrant keratinocyte differentiation markers. This can be inhibited by the AP-1 inhibitor tanshinone IIA. Loss of RAC1 makes keratinocytes hypersensitive to inflammatory stimuli both in vitro and in vivo, suggesting a major role for RAC1 in regulating the crosstalk between the epidermis and the immune system.
authors.affiliation: Biomedical Institute, BRIC, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen,  Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Pedersen
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Alanna
authors.initials: A
authors.lastname: Stanley
authors.forename: Karine
authors.initials: K
authors.lastname: Peyrollier
authors.forename: Lennart M
authors.initials: LM
authors.lastname: Rösner
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
authors.forename: Fabio
authors.initials: F
authors.lastname: Quondamatteo
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
mesh_terms: D045784:Abietanes / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D045784:Abietanes; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C021751:tanshinone; D007371:Interferon-gamma; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate