Dendritic Cells as Sensors, Mediators, and Regulators of Ischemic Injury

Abstract

Dendritic cells (DCs) are highly specialized, bone marrow (BM)-derived antigen-processing and -presenting cells crucial to the induction, integration and regulation of innate, and adaptive immunity. They are stimulated by damage-associated molecular patterns (DAMPS) via pattern recognition receptors to promote inflammation and initiate immune responses. In addition to residing within the parenchyma of all organs as part of the heterogeneous mononuclear phagocyte system, DCs are an abundant component of the inflammatory cell infiltrate that appears in response to ischemia reperfusion injury (IRI). They can play disparate roles in the pathogenesis of IRI since their selective depletion has been found to be protective, deleterious, or of no benefit in mouse models of IRI. In addition, administration of DC generated and manipulated ex vivo can protect organs from IRI by suppressing inflammatory cytokine production, limiting the capacity of DCs to activate NKT cells, or enhancing regulatory T cell function. Few studies however have investigated specific signal transduction mechanisms underlying DC function and how these affect IRI. Here, we address current knowledge of the role of DCs in regulation of IRI, current gaps in understanding and prospects for innovative therapeutic intervention at the biological and pharmacological levels.

Keywords: dendritic cells; heart; ischemic injury; kidney; liver.

Figure 1

The DC interactome following renal ischemia reperfusion injury (IRI). IRI is a common clinical condition triggered by various physiological derangements including sepsis, cardiogenic shock, vascular surgery, and organ retrieval for transplantation. Following injury, resident, and influxing DCs become activated within the kidney parenchyma and are the dominant TNFα-producing cells. The effect of TNF-α is dependent on the transcription factor IRF-4, promoting renal tubular epithelial cell apoptosis, glomerular endothelial damage, and fibrin deposition. Post-IRI, intra-renal DCs upregulate markers that designate them as mature APCs, including MHC, CD80, CD86, CD40, and CD1d. Activation of NKT cells via CD40 initiates IFN-g to amplify the innate immune response. Renal DCs are capable of presenting self-Ag to a variety of T cells in the context of IRI: CD11c⁺ DCs cross-present Ag to CD8⁺ T cells and glycolipids are presented to NKT cells via CD1d. Exposure of DCs to hypoxia/reperfusion augments production of IL-12 and IL-6, and an inflammatory T cell phenotype through HIF-1α transcriptional regulation. Absence of DC-specific HIF-1α limits expression of IL-10 and TGF-β, which are potent inducers of Tregs. DCs intercommunicate with neutrophils and NKT cells to enhance tissue injury through chemokine/cytokine secretion, as well as cell-based contact. Neutrophils release ROS and proteolytic enzymes, and NK1.1⁺CD161⁺ NKT cells elaborate pro-inflammatory cytokines and are the predominant early inflammatory cells that impair organ function within hours of IRI. Ag, antigen; DAMPs, damage-associated molecular patterns; HIF-1, hypoxia-inducible factor-1; IRF-4, interferon regulatory factor-4; ROS, reactive oxygen species.