Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression.
The retinoid X receptor alpha (RXRalpha) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRalpha regulates the transcription of the chemokines Ccl6 and Ccl9 in macrophages independently of heterodimeric partners. Mice lacking RXRalpha in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRalpha plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.
Núñez
Vanessa
V
Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.
Alameda
Daniel
D
Rico
Daniel
D
Mota
Rubén
R
Gonzalo
Pilar
P
Cedenilla
Marta
M
Fischer
Thierry
T
Boscá
Lisardo
L
Glass
Christopher K
CK
Arroyo
Alicia G
AG
Ricote
Mercedes
M
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047490:Retinoid X Receptor alpha / Q000172:deficiency / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D014158:Transcription, Genetic; D015854:Up-Regulation
C095218:Ccl9 protein, mouse; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D047490:Retinoid X Receptor alpha; C070959:Ccl6 protein, mouse