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TRPV4-MEDIATED DETECTION OF HYPOSMOTIC STRESS BY SKIN KERATINOCYTES ACTIVATES DEVELOPMENTAL IMMUNITY
Autores:
JORGE GALINDO VILLEGAS
,
VICTORIANO MULERO MÉNDEZ
,
Grupos de investigación:
[GI/IMIB/C060/2011] Inmunidad, inflamación y cáncer
Comunicación:
Antecedentes:
By the time in which an organism is exposed to pathogens during very early development, specific defense mechanisms must take effect immediately. Despite recent progress using gnotobiotic models, the full set of molecular pathways orchestrating inflammation and immunity in vertebrate organisms which not have fully achieved immune system maturation remains an ongoing challenge. Through this study, we demonstrate that skin keratinocytes play a critical role on the activation of immunity and host protection in newly hatched embryos.
Métodos:
Following our established protocol, germ-free (GF) zebrafish embryos were generated. At 24 or 48 h post fertilization (hpf) eggs were manually dechorionated and the free-swimming embryos subjected for a short period to independent saline solutions along a gradient, ranging from iso to hyperosmotic (280 and 400 mOsm/l). Also, some GF eggs were either microinjected with TRPV4 splice blocking morpholino, or treated with pharmacological drugs to recapitulate or inhibit the sensing of osmolarity and the intracellular downstream mechanisms. To achieve our goal, gene expression analysis, whole-mount immunofluorescence, infection assays against Salmonella enterica serovar Typhimurium (ST) and extracellular or cytosolic Ca2+ assays were performed.
Resultados:
Skin keratinocytes were responsible for sensing the hyposmolarity of the aquatic environment and mediating immune effector mechanisms mediated by a transient potential receptor vanilloid 4/Ca2+/TGF-b–activated kinase 1/NF-kB. This resulted in a major IL-1b up-regulation along with a wide set of pro-inflammatory genes. However, the genes encoding antimicrobial effectors, which do not have the potential to cause tissue damage, are constitutively expressed during development, independently of both commensal microbes and osmotic stress. Interestingly, a short activation mediated by the hypotonic media leads to increased resistance against the pathogenic bacterium ST in a MyD88-independent manner.
Conclusiones:
Results provided evidence that osmotic stress is associated with the induction of developmental immunity in the absence of tissue damage and, clearly point out to the embryo skin as the first organ with full capacities to mount an innate immune response. Additionally, these findings also reveal that drugs targeting TRPV4 channel or the associated signaling pathway are promising tools for reduction of skin inflammatory disorders, such as psoriasis and atopic dermatitis.
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