TY - JOUR

T1 - RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3-dependent control of STAT1

AU - Pedersen, Esben Ditlev Kølle

AU - Wang, Zhipeng

AU - Stanley, Alanna

AU - Peyrollier, Karine

AU - Rösner, Lennart M

AU - Werfel, Thomas

AU - Quondamatteo, Fabio

AU - Brakebusch, Cord Herbert

PY - 2012/11/15

Y1 - 2012/11/15

N2 - 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.

AB - 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.

KW - Actin Cytoskeleton

KW - Actin-Related Protein 2-3 Complex

KW - Actins

KW - Animals

KW - Cell Differentiation

KW - Diterpenes, Abietane

KW - Enzyme Activation

KW - Epidermis

KW - Gene Expression Regulation

KW - Inflammation

KW - Interferon-gamma

KW - Keratinocytes

KW - Leukocytes

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neuropeptides

KW - Polymerization

KW - STAT1 Transcription Factor

KW - Signal Transduction

KW - Skin

KW - Tetradecanoylphorbol Acetate

KW - rac GTP-Binding Proteins

KW - rac1 GTP-Binding Protein

U2 - 10.1242/jcs.107011

DO - 10.1242/jcs.107011

M3 - Journal article

C2 - 22956547

VL - 125

SP - 5379

EP - 5390

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - Pt 22

ER -