Dendritic cell migration in inflammation and immunity

Abstract

Dendritic cells (DCs) are the key link between innate immunity and adaptive immunity and play crucial roles in both the promotion of immune defense and the maintenance of immune tolerance. The trafficking of distinct DC subsets across lymphoid and nonlymphoid tissues is essential for DC-dependent activation and regulation of inflammation and immunity. DC chemotaxis and migration are triggered by interactions between chemokines and their receptors and regulated by multiple intracellular mechanisms, such as protein modification, epigenetic reprogramming, metabolic remodeling, and cytoskeletal rearrangement, in a tissue-specific manner. Dysregulation of DC migration may lead to abnormal positioning or activation of DCs, resulting in an imbalance of immune responses and even immune pathologies, including autoimmune responses, infectious diseases, allergic diseases and tumors. New strategies targeting the migration of distinct DC subsets are being explored for the treatment of inflammatory and infectious diseases and the development of novel DC-based vaccines. In this review, we will discuss the migratory routes and immunological consequences of distinct DC subsets, the molecular basis and regulatory mechanisms of migratory signaling in DCs, and the association of DC migration with the pathogenesis of autoimmune and infectious diseases.

Keywords: autoimmune diseases; cell migration; chemokine receptor CCR7; dendritic cells; inflammation.

Fig. 1. DC migration in the regulation of immune defense and homeostasis.

Dendritic cells can be divided into various subpopulations with significant phenotypic heterogeneity and functional plasticity. The major DC subsets, including conventional DCs (cDCs), monocyte-derived DCs (moDCs), plasmacytoid DCs (pDCs) and Langerhans cells (LCs), follow distinct migratory routes and exhibit different migratory properties and consequently exert various immunological and inflammatory functions. (1) Preconventional dendritic cells (pre-cDCs) give rise to immature cDCs (cDC1s and cDC2s), which undergo maturation and express high levels of CCR7 upon stimulation by pathogenic or inflammatory signals. CCR7 interacts with its ligands CCL19 and CCL21 to guide mature cDC trafficking toward lymph nodes via afferent lymphatics to regulate T-cell immunity. Semimature cDCs also express CCR7 under steady-state conditions and migrate to lymph nodes to induce the activation of regulatory T cells and maintenance of immune tolerance against self-antigens or inhaled and food antigens. cDC1s potently cross-prime CD8⁺ T cells for viral clearance and activation of the Th1/Th17 response to protect against bacteria. CCR7 and CCR8 mediate cDC2 trafficking to the lymph node parenchyma to initiate a Th2 cell-dependent allergic immune response. (2) Blood Ly6C^hi monocytes are recruited to inflamed skin or lymphoid tissues via CCR2 and become monocyte-derived DCs (moDCs), which stimulate Th1 or Th2 responses, contributing to local inflammation. CX₃CR1^intLy6C^lo moDCs at the lamina propria migrate toward lymph nodes via CCR7 ligation during colon inflammation. (3) Plasmacytoid DC (pDC) recruitment from the blood to the lymph nodes or the small intestine is regulated by CCR7 and CCR9, respectively. CCR2 and CXCR3 are also important for the trafficking and distribution of pDCs. After CCR7-mediated extravasation into lymphoid tissues, pDCs are instructed to express CCR6 and CCR10, which mediate their migration to inflamed skin for IFN-α production and facilitate pathogen clearance and local inflammation. (4) LCs are localized in the epidermis and efficiently migrate to skin-draining lymph nodes following inflammatory stimulation in a manner dependent on CCR7 and CXCR4. LCs not only induce T-cell activation during skin inflammation but also mediate the inhibition of T-cell function and the induction of regulatory T cells

Fig. 2. Molecular regulation of DC migration.

Multiple levels of intracellular regulators are employed to modulate the signaling pathways induced by chemokines to ensure the most beneficial outcome of DC migration in the regulation of immunity and tolerance. (1) Protein modification (shown in yellow boxes and arrows). CCL19 and CCL21 stimulation induces the phosphorylation of CCR7, β-arrestin, MAPK/ERK, p38 and JNK successively, which is crucial for DC chemotaxis and migration. Polysialylation of CCR7 is essential for recognition of its ligand CCL21 and therefore controls CCR7-mediated DC migration. (2) Epigenetic reprogramming (shown in blue boxes and arrows). Migratory cDCs and nonmigratory moDCs show different levels of H3K27me3 modifications at the CCR7 gene locus. Setdb2 induces the generation of H3K9me3 (a repressive marker) at the Cxcl1 gene promoter, leading to reduced neutrophil infiltration and inhibited host defense against bacterial superinfection. SIRT6 promotes CXCR4⁺ DC migration to the afferent lymph nodes via its effects on monitoring H3K9 acetylation. Ezh2 directly mediates methylation of the cytoplasmic integrin adaptor talin, disrupting the binding of talin to F-actin, thereby promoting the extravasation and motility of DCs under inflammatory conditions. The long-noncoding RNA lnc-Dpf3 directly binds to the transcription factor HIF-1α and suppresses HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. (3) Metabolic remodeling (shown in green boxes and arrows). Glycolytic metabolism is essential for CCR7 oligomerization and DC migration, and glycolytic NAD⁺ supports DC migration by maintaining F-actin polarization and polymerization. Resolvin E1 inhibits DC motility and migration and attenuates the contact hypersensitivity response by disrupting actin polymerization. (4) Cytoskeleton rearrangement (shown in dark red boxes and arrows). Actin polymerization and retrograde flow at the front and actinomyosin contraction at the rear determine cell polarity and provide the driving forces of DC migration. The phosphoinositide transferase protein TIPE2 plays dual roles in signaling regulation by inhibiting Rac-dependent actin polymerization at the rear but enhancing PI3K-dependent actin polymerization at the front, thus facilitating cytoskeleton remodeling and leading-edge formation. The ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1) is activated for lysosomal calcium release, leading to rearrangement of the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration