S1PR4 is required for plasmacytoid dendritic cell differentiation

Abstract

The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1-5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question of whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient vs. wildtype mice. This effect was not caused by altered migration of mature pDC, but rather a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. As S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity.

Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

“…38 Another S1P receptor subtype, S1PR1 , plays an important role in regulating immune cell function and lymphocyte trafficking by regulating egress of lymphocytes from bone marrow and lymphoid tissues; 39–41 however, much less is known about the function of S1PR4. S1PR4 is expressed on hematopoietic and lymphoid cells and has been implicated in terminal megakaryocyte differentiation to platelets, 42 and the regulation of dendritic cell function and T(H)17-cell 43 and plasmacytoid dendritic cell 44 differentiation. S1PR4 is highly expressed in neutrophils and lymphocytes.…”

Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation

“…Within the DC lineage, murine pDCs nearly exclusively express S1PR4 among S1P receptors [ 81 ]. In a study initially designed to look at S1P-dependent migration of murine pDCs, it was noted that S1PR4-deficient mice specifically lack the subpopulation of migratory CD4 − pDCs in blood and primary as well as secondary hematopoietic organs [ 82 ]. Frequencies of other immune cells were not affected.…”

“…While S1PR4 did not modify pDC migration, it appeared to specifically promote the migration of common dendritic cell precursors (CDPs) towards S1P in vitro . This was correlated with an accumulation of CDPs in murine S1PR4-deficient bone marrow compared to WT bone marrow [ 82 ]. A possible explanation for this correlation is the observation that pDCs develop in regions with high oxygen in the bone marrow, indicated by the fact that hypoxia-inducible factor-1 limits pDC development [ 83 ], which are likely enriched in vasculature and therefore in contact with the high levels of S1P in the circulation.…”

Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment

“…Expressions of S1PR4/5 are more limited, and the mechanisms that they regulate are less understood. However, it is known that S1PR4 promotes neutrophil trafficking ( 30 ) and dentritic cell differentiation ( 31 ), while S1PR5 has been associated with natural killer (NK) cell trafficking ( 32 , 33 ).…”