Divergent effects of hypoxia on dendritic cell functions

Abstract

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 upregulates production of proinflammatory cytokines, particularly TNF␣ and IL-1␤, 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. (Blood. 2008;112:3723-3734) IntroductionLow oxygen tension (hypoxia) has been described at virtually every site of extensive inflammation, including necrotic foci and cutaneous sites of infection and wounding. 1 Sites of inflammation are also characterized by extensive infiltration of inflammatory leukocytes, which need to move against oxygen gradients. As a consequence, immune effector cells in hypoxic sites, including dendritic cells (DCs), have an acute need to respond to these demanding conditions to maintain their viability and activity. DCs are powerful antigen-presenting cells (APCs) specialized for the activation of resting T cells and the initiation and regulation of many types of immune response. [2][3][4][5] Because of this, we have investigated the functional changes that accompanying the metabolic adaptation of DCs to hypoxia, as these events are likely to affect the development of both inflammatory and immune functions.The capacity of DCs to activate and regulate T-cell responses is acquired during a complex differentiation and maturation program. [2][3][4][5] DCs originate from bone marrow and, at an "immature" stage, they patrol peripheral tissues for the presence of pathogenassociated antigens. In order to perform this function, DCs express a rich repertoire of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), which permit DCs to recognize distinct pathogen-associated molecules. 6,7 The engagement of TLRs initiates a cascade of signaling events in DCs that leads, in the process of "maturation," to the secretion of inflammatory and immunomodulatory factors, which mediate protective immunity. 6,7 For instance, stimulation of DC by lipopolysaccharide (LPS), through the participation of TLR4, lead...

The transcription factor NR4A3 controls CD103+ dendritic cell migration

“…We investigated gut pathology in the small intestine, cecum, and colon of these mice at approximately 8 to 12 weeks of age and found no evidence of colitis unable to efficiently migrate to LNs (60). Although a link between energy metabolism and CCR7 regulation exists in the literature (57-59), it is not clear from our studies that NR4A3 directly regulates CCR7 through changes in energy metabolism.…”

Hypoxia: jump-starting inflammation

“…DCs are a heterogeneous group of professional antigen-presenting cells that are essential to link innate to adaptive immunity, by recognizing danger signals and triggering T-cell responses. Evidence has been provided that hypoxia may either impair 9 or promote 10 DC function. In this issue, Bosco et al 1 provide a detailed analysis of the transcriptional profile of monocyte-derived mature DCs cultured under hypoxic conditions (H-mDCs).…”

Role of the Hypoxia-Inducible Factor in Periodontal Inflammation

“…Studies found that the knockdown of HIF-1α in DCs inhibited their maturation and signiicantly impaired their capability to stimulate allogeneic T cells, probably because of the reliance on the HIF-controlled glycolysis [64,65]. In contrast, it is reported that low oxygen tension inhibited the DCs' defense against LPS, but strongly upregulated the production of proinlammatory cytokines in the cells involved [66]. Similar results can be observed in the human antifungal response: hypoxia at the site of Aspergillus fumigatus infection inhibited the full activation and function of DCs [67].…”