Efferocytosis in dendritic cells: an overlooked immunoregulatory process

Abstract

Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.

Keywords: Treg differentiation; antigen cross-presentation; apoptotic cell; dendritic cell; efferocytosis; immune regulation.

Figure 1

Apoptotic Cell Recognition, Internalization, and Degradation Pathways in Phagocytic Cells. This illustration depicts the signaling pathways activated for cytoskeletal rearrangement and apoptotic cell degradation following the recognition of apoptotic cells on the surfaces of phagocytic cells. Upon the binding of phosphatidylserine (PS) on apoptotic cells, surface receptors such as Stabilin2, BAI1, AXL, and integrin αvβ5 on phagocytic cells initiate signaling cascades. These cascades activate Rho GTPases, including RhoA, Rac1, and Cdc42, which subsequently trigger various downstream effectors. Activation of RhoA leads to the ROCK-mediated phosphorylation of MLC via MLCP, influencing actin polymerization, which is crucial for the formation of the phagocytic cup. Rac1 and Cdc42 facilitate actin assembly through mDia and the WAVE/Arp2/3 complex, respectively, enhancing the engulfment and internalization of apoptotic cells. After internalizing apoptotic cells, the maturation and degradation pathways commence. The microtubule-tip-associated protein EB1 transports the GEF Gapex-5 to the efferosome membrane, activating Rab5-GDP. The activated Rab5-GTP further promotes the activation of Vps34, leading to the production of PtdIns(3)P on the efferosome surface. This PtdIns(3)P subsequently recruits the effector protein Eea1 (Early Endosome Antigen 1), enhancing the fusion of efferosomes with early endosomes. At this point, the efferosome begins to acidify. The next step involves the Mon1-Ccz1 complex recruiting and activating Rab7 on the efferosome. Rab7 recruits the effector protein RILP, which in turn recruits and interacts with the HOPS complex, facilitating the sequential fusion of the early efferosome with late endosomes and lysosomes, ultimately forming the effero-lysosome. At this stage, the efferosome becomes increasingly acidic, activating acidic proteases and nucleases, beginning the degradation of apoptotic cell contents. Rab17 drives the division of effero-lysosomes into smaller vesicles and directs these vesicles to merge with recycling endosomes near the cell membrane, promoting material recycling and distancing from MHC-II.

Figure 2

Dendritic Cell Subtypes and Their Markers and Functions. This figure illustrates the distinct subsets of dendritic cells, detailing their specific cell markers and functional roles in immune responses.

Figure 3

The Anti-Inflammatory Effects of TAM Receptor and LXR Signaling Pathways in Dendritic Cell Efferocytosis. Toll-like receptors (TLRs) are located on the cell membrane and are capable of recognizing various molecules such as lipopolysaccharides (LPS), double-stranded DNA (dsDNA), CpG, and single-stranded RNA (ssRNA). The binding of these molecules to TLRs triggers a series of signal transduction pathways, activating a set of proteins including MyD88, TRIF, TRAF3, TRAF6, TAK1, TAB1/2, and IκK. During this process, the IκK complex phosphorylates IκB protein, leading to its degradation and the release of NF-κB. Subsequently, NF-κB enters the cell nucleus and initiates the transcription of inflammatory factors. Meanwhile, when dendritic cells (DCs) recognize and bind to apoptotic cells through TAM receptors and bridging molecules, TAMs receptors are activated. The activated TAMs receptors, with the assistance of SOCS1/3, STAT1, and type I interferons, inhibit the inflammatory signaling induced by TLRs activation. This includes suppressing the activation of TRAF3/6 and IκK, as well as the degradation of IκBα, thereby inhibiting the NF-κB signaling pathway and preventing excessive inflammation. Upon the engulfment of apoptotic cells by DCs, the LXRβ is activated, leading to the upregulation of genes involved in cholesterol efflux, notably Abcg1 and ApoE. This upregulation facilitates the efflux of cholesterol from the engulfed apoptotic cells to the extracellular matrix. This mechanism not only mitigates the accumulation of cholesterol but also suppresses the transcription of pro-inflammatory cytokines. Additionally, activation of the LXR signaling pathway promotes the transcription of CCR7, enhancing the migration capabilities of tolerogenic dendritic cells, thus contributing to the maintenance of immune homeostasis.

Figure 4

DC phagocytosis induces Treg differentiation and enhances its function. When immature dendritic cells (DCs) engulf apoptotic cells, they undergo a transformation into tolerogenic DCs. This transformation is marked by a reduction in the expression of co-stimulatory molecules. These tolerogenic DCs then produce and release immune-modulating substances such as IL10, TGF-beta, and retinoic acid (RA). The IL10 secreted by tolerogenic DCs binds to IL10 receptors on regulatory T cells (Tregs), which enhances the Tregs’ ability to function effectively. On the other hand, TGF-beta and RA work together in the presence of IL2 and integrins αvβ8 to drive the differentiation of naive T cells into regulatory T cells. These regulatory T cells play a crucial role in establishing and maintaining immune tolerance. They achieve this by releasing anti-inflammatory mediators, which help in preventing overactive immune responses that could lead to autoimmunity or chronic inflammation.