Maturing Dendritic Cells Depend on RAGE for In Vivo Homing to Lymph Nodes

Abstract

The mobilization of dendritic cells (DCs) from peripheral tissues is critical for the establishment of T cell-dependent immune responses or tolerance, because the physical interaction of DCs with naive T cells takes place in the T cell areas of lymph nodes. The autocrine/paracrine release of the high mobility group box 1 (HMGB1) nuclear protein by DCs controls the outcome of the DC–T cell interaction, influencing the priming/Th1 polarization of naive T cells. We herein present evidence that the receptor for advanced glycation end products (RAGE), a multiligand member of the Ig superfamily of cell-surface molecules that acts as a receptor for HMGB1, plays a nonredundant role in DC homing to lymph nodes. We used noninvasive imaging by magnetic resonance and immunohistochemistry to track DCs after s.c. injection in the footpad of wild-type+/+ or RAGE−/− mice. Maturing DCs expressing RAGE effectively migrated in both conditions. In contrast, RAGE−/− DCs failed to reach the draining popliteal lymph nodes of +/+ and −/− mice, indicating that the integrity of RAGE is required for DC mobilization. Thus the HMGB1-RAGE pathway is a checkpoint in DC maturation and function and a candidate for targeted therapies.

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Other studies, however, indicate a direct effect of RAGE on mobilisation of dendritic cells [79] and T cell migration, localisation, activation and differentiation [35,75,80], whereas HMGB1 signalling through RAGE seems to be required for clonal expansion, survival and functional polarisation of naive T cells [81]. Furthermore, clonal populations of Rage −/− mice-derived T cells adoptively Monocytes and macrophages seem to be central to the initiation and propagation of RAGE-dependent inflammation transferred into wild-type recipients showed reduced responses [82].…”

Novel insights for high mobility group box 1 protein-mediated cellular immune response in sepsis:A systemic review

“…[48] The HMGB1-RAGE pathway is a checkpoint in DCs maturation and function and a candidate for targeted therapies. [49] Nontheless, current evidences suggest that RAGE alone could not explain all the effects of HMGB1, as discrepancies exist between specific HMGB1-binding/ RAGE activation and biological effects of HMGB1. Recent data indicate that TLR4, a pivotal receptor for activation of innate immunity and cytokine release, may also play a role in HMGB1 signaling.…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…HMGB1 aktiviert ü ber Bindung an RAGE dendritische Zellen und f ö rdert ihre Reifung, was zur Aussch ü ttung von proinflammatorischen Zytokinen wie IL-1-α , IL-6 und TNF-α f ü hrt. Dar ü ber hinaus wird das " homing " der dendritischen Zellen in die Lymphknoten angeregt und so die T-Zell-Differenzierung gef ö rdert [64,65] .…”