Divergent effects of hypoxia on dendritic cell functions.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that patrol tissues to sense danger signals and activate specific immune responses. In addition, they also play a role in inflammation and tissue repair. Here, we show that oxygen availability is necessary to promote full monocyte-derived DC differentiation and maturation. Low oxygen tension (hypoxia) inhibits expression of several differentiation and maturation markers (CD1a, CD40, CD80, CD83, CD86, and MHC class II molecules) in response to lipopolysaccharide (LPS), as well as their stimulatory capacity for T-cell functions. These events are paralleled by impaired up-regulation of the chemokine receptor CCR7, an otherwise necessary event for the homing of mature DCs to lymph nodes. In contrast, hypoxia strongly up-regulates production of proinflammatory cytokines, particularly TNFalpha and IL-1beta, as well as the inflammatory chemokine receptor CCR5. Subcutaneous injection of hypoxic DCs into the footpads of mice results in defective DC homing to draining lymph nodes, but enhanced leukocyte recruitment at the site of injection. Thus, hypoxia uncouples the promotion of inflammatory and tissue repair from sentinel functions in DCs, which we suggest is a safeguard mechanism against immune reactivity to damaged tissues.
Mancino
Alessandra
A
Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
Schioppa
Tiziana
T
Larghi
Paola
P
Pasqualini
Fabio
F
Nebuloni
Manuela
M
Chen
I-Hsuan
IH
Sozzani
Silvano
S
Austyn
Jonathan M
JM
Mantovani
Alberto
A
Sica
Antonio
A
D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000276:immunology* / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051193:Toll-Like Receptors