Try a new search

Format these results:

Searched for:



Total Results:


S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes

Dixit, Dhaval; Hallisey, Victoria M; Zhu, Ethan Ys; Okuniewska, Martyna; Cadwell, Ken; Chipuk, Jerry E; Axelrad, Jordan E; Schwab, Susan R
Effective immunity requires a large, diverse naive T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization were required to prevent this proapoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naive T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.
PMID: 38194271
ISSN: 1558-8238
CID: 5635202

Get me out of here: Sphingosine 1-phosphate signaling and T cell exit from tissues during an immune response

Hallisey, Victoria M; Schwab, Susan R
During an immune response, the duration of T cell residence in lymphoid and non-lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1-phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G-protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.
PMID: 37212181
ISSN: 1600-065x
CID: 5543562

Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney

Tanaka, Shinji; Zheng, Shuqiu; Kharel, Yugesh; Fritzemeier, Russell G; Huang, Tao; Foster, Daniel; Poudel, Nabin; Goggins, Eibhlin; Yamaoka, Yusuke; Rudnicka, Kinga P; Lipsey, Jonathan E; Radel, Hope V; Ryuh, Sophia M; Inoue, Tsuyoshi; Yao, Junlan; Rosin, Diane L; Schwab, Susan R; Santos, Webster L; Lynch, Kevin R; Okusa, Mark D
Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.
PMID: 35976996
ISSN: 1946-6242
CID: 5299962

Blood-thirsty: S1PR5 and TRM

Hallisey, Victoria M; Schwab, Susan R
In this elegant study, Evrard et al. (2021. J. Exp. Med. find that sphingosine 1-phosphate receptor 5 (S1PR5) powerfully impairs tissue-resident memory T cell (TRM) formation, and that tissue-derived TGF-β limits S1pr5 expression by infiltrating T cells.
PMID: 34714328
ISSN: 1540-9538
CID: 5042852

Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

Sano, Teruyuki; Kageyama, Takahiro; Fang, Victoria; Kedmi, Ranit; Martinez, Carlos Serafin; Talbot, Jhimmy; Chen, Alessandra; Cabrera, Ivan; Gorshko, Oleksandra; Kurakake, Reina; Yang, Yi; Ng, Charles; Schwab, Susan R; Littman, Dan R
Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.
PMID: 34433045
ISSN: 2211-1247
CID: 4989122

SPNS2 enables T cell egress from lymph nodes during an immune response

Okuniewska, Martyna; Fang, Victoria; Baeyens, Audrey; Raghavan, Varsha; Lee, June-Yong; Littman, Dan R; Schwab, Susan R
T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables T cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic T cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables T cell exit, while the transporter MFSD2B supplies most blood S1P and supports vascular function. It is unknown whether SPNS2 remains necessary to supply lymph S1P during an immune response, or whether in inflammation other compensatory transporters are upregulated. Here, using a model of dermal inflammation, we demonstrate that SPNS2 supplies the S1P that guides T cells out of LNs with an ongoing immune response. Furthermore, deletion of Spns2 is protective in a mouse model of multiple sclerosis. These results support the therapeutic potential of SPNS2 inhibitors to achieve spatially specific modulation of S1P signaling.
PMID: 34260944
ISSN: 2211-1247
CID: 4965312

Nilabh Shastri 1952-2021 [Obituary]

Hammer, Gianna E; Schwab, Susan R; Sun, Joseph C
PMID: 33782613
ISSN: 1529-2916
CID: 4840862

Monocyte-derived S1P in the lymph node regulates immune responses

Baeyens, Audrey; Bracero, Sabrina; Chaluvadi, Venkata S; Khodadadi-Jamayran, Alireza; Cammer, Michael; Schwab, Susan R
The lipid chemoattractant sphingosine 1-phosphate (S1P) guides cells out of tissues, where the concentration of S1P is relatively low, into circulatory fluids, where the concentration of S1P is high1. For example, S1P directs the exit of T cells from lymph nodes, where T cells are initially activated, into lymph, from which T cells reach the blood and ultimately inflamed tissues1. T cells follow S1P gradients primarily using S1P receptor 1 (ref. 1). Recent studies have described how S1P gradients are established at steady state, but little is known about the distribution of S1P in disease or about how changing levels of S1P may affect immune responses. Here we show that the concentration of S1P increases in lymph nodes during an immune response. We found that haematopoietic cells, including inflammatory monocytes, were an important source of this S1P, which was an unexpected finding as endothelial cells provide S1P to lymph1. Inflammatory monocytes required the early activation marker CD69 to supply this S1P, in part because the expression of CD69 was associated with reduced levels of S1pr5 (which encodes S1P receptor 5). CD69 acted as a 'stand-your-ground' signal, keeping immune cells at a site of inflammation by regulating both the receptors and the gradients of S1P. Finally, increased levels of S1P prolonged the residence time of T cells in the lymph nodes and exacerbated the severity of experimental autoimmune encephalomyelitis in mice. This finding suggests that residence time in the lymph nodes might regulate the differentiation of T cells, and points to new uses of drugs that target S1P signalling.
PMID: 33658712
ISSN: 1476-4687
CID: 4801642

Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke

Nitzsche, Anja; Poittevin, Marine; Benarab, Ammar; Bonnin, Philippe; Faraco, Giuseppe; Uchida, Hiroki; Favre, Julie; Garcia-Bonilla, Lidia; Garcia, Manuela C L; Léger, Pierre-Louis; Thérond, Patrice; Mathivet, Thomas; Autret, Gwennhael; Baudrie, Véronique; Couty, Ludovic; Kono, Mari; Chevallier, Aline; Niazi, Hira; Tharaux, Pierre-Louis; Chun, Jerold; Schwab, Susan R; Eichmann, Anne; Tavitian, Bertrand; Proia, Richard L; Charriaut-Marlangue, Christiane; Sanchez, Teresa; Kubis, Nathalie; Henrion, Daniel; Iadecola, Costantino; Hla, Timothy; Camerer, Eric
RATIONALE/BACKGROUND:modulation in stroke. OBJECTIVE:in the naive and ischemic brain and its potential as a target for cerebrovascular therapy. METHODS AND RESULTS/RESULTS:-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. CONCLUSIONS:agonists.
PMID: 33301355
ISSN: 1524-4571
CID: 4799282

Finding a Way Out: S1P Signaling and Immune Cell Migration

Baeyens, Audrey A L; Schwab, Susan R
The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in an immune response. Drugs targeting S1P signaling have been remarkably successful in treatment of multiple sclerosis, and they have shown promise in clinical trials for colitis and psoriasis. One mechanism of these drugs is to block lymphocyte exit from lymph nodes, where lymphocytes are initially activated, into circulation, from which lymphocytes can reach sites of inflammation. Indeed, S1P can be considered a circulation marker, signaling to immune cells to help them find blood and lymphatic vessels, and to endothelial cells to stabilize the vasculature. That said, S1P plays pleiotropic roles in the immune response, and it will be important to build an integrated view of how S1P shapes inflammation. S1P can function so effectively because its distribution is exquisitely tightly controlled. Here we review how S1P gradients regulate immune cell exit from tissues, with particular attention to key outstanding questions in the field.
PMID: 32340572
ISSN: 1545-3278
CID: 4427682