Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin.
To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRalphabeta(ep-/-) somatic mutants in which both RXRalpha and RXRbeta are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRalphabeta-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRalphabeta-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.
Li
Mei
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Collège de France, BP10142, 1 Rue Laurent Fries, Illkirch 67404, CU de Strasbourg, France.
Messaddeq
Nadia
N
Teletin
Marius
M
Pasquali
Jean-Louis
JL
Metzger
Daniel
D
Chambon
Pierre
P
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000235:genetics*; D005838:Genotype; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047488:Retinoid X Receptors / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D007074:Immunoglobulin G; D047488:Retinoid X Receptors; D007073:Immunoglobulin E; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse