Abstract
Signaling lymphocyte activation molecule family (SLAMF) receptors are essential regulators of innate and adaptive immune responses. The function of SLAMF5/CD84, a family member with almost ubiquitous expression within the hematopoietic lineage is poorly defined. In this article, we provide evidence that in human monocyte-derived dendritic cells (moDCs) SLAMF5 increases autophagy, a degradative pathway, which is highly active in dendritic cells (DCs) and plays a critical role in orchestration of the immune response. While investigating the underlying mechanism, we found that SLAMF5 inhibited proteolytic degradation of interferon regulatory factor 8 (IRF8) a master regulator of the autophagy process by a mechanism dependent on the E3-ubiquitin ligase tripartite motif-containing protein 21 (TRIM21). Furthermore, we demonstrate that SLAMF5 influences the ratio of CD1a+ cells in differentiating DCs and partakes in the regulation of IL-1β, IL-23, and IL-12 production in LPS/IFNγ-activated moDCs in a manner that is consistent with its effect on IRF8 stability. In summary, our experiments identified SLAMF5 as a novel cell surface receptor modulator of autophagy and revealed an unexpected link between the SLAMF and IRF8 signaling pathways, both implicated in multiple human pathologies.
Highlights
Macroautophagy is a conserved catabolic pathway, whereby cytosolic contents are sequestered by de novo formed double-membrane-bound vesicles, called autophagosomes and carried to lysosomes for degradation
We found that SLAMF5 is strongly induced when monocytes are differentiated into Dendritic cells (DCs) by GM-CSF and IL-4 suggesting that SLAMF5 is required for the proper functions of immature DCs (Figure 1A)
Binsky et al have recently published that SLAMF5 acts as a survival receptor in chronic lymphocytic leukemia cells and its downregulation results in receptor induced cell death [31], under our experimental conditions neither the viability of monocyte-derived dendritic cells (moDCs) nor the yield of differentiation was affected by SLAMF5 silencing (Figure 1C)
Summary
Macroautophagy (here referred to as autophagy) is a conserved catabolic pathway, whereby cytosolic contents are sequestered by de novo formed double-membrane-bound vesicles, called autophagosomes and carried to lysosomes for degradation It is active at basal levels in most cell types to recycle macromolecules [1, 2] and to prevent accumulation of cytotoxic metabolites [3]. DCs exploit autophagy to display cytoplasmic self- or foreign antigens on MHC II molecules for CD4+ T cells [10] This mechanism, depending on the presence or absence of danger signal-induced co-stimulation, contributes to the initiation of a pathogen-specific immune response and to establishment or maintenance of peripheral tolerance, respectively [11]. As all immune responses, including TLR-mediated functions have the potential to convey damage to host tissues, the recovery of autophagy, reestablishing its anti-inflammatory effects is increasingly recognized as an essential component of the maintenance of host tissue integrity
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