Monocyte-derived S1P in the lymph node regulates immune responses

Baeyens, Audrey; Bracero, Sabrina; Chaluvadi, Venkata; Khodadadi‐Jamayran, Alireza; Cammer, Michael; Schwab, Susan R.

doi:10.1038/s41586-021-03227-6

Cited by 51 publications

(61 citation statements)

References 37 publications

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“…This argues against the role of endothelial cells for the novel source of S1P. A recent study suggests that inflammatory monocytes secrete S1P during immune responses (Baeyens et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and protection of anaphylaxis

Nguyen

Yen

et al. 2021

Preprint

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SummarySphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types to induce signaling. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells, which contributes approximately 50% plasma S1P. To further determine the sources of plasma S1P, here, we report the characterizations of compound deletions of Mfsd2b and Spns2, another S1P transporter from endothelial cells. Global deletion of Mfsd2b and Spns2 (gDKO) resulted in embryonic lethality between E13.5 and E14.5 with severe hemorrhage that largely recapitulated the phenotypes from global S1P1 knockout mice, indicating that together with Mfsd2b, Spns2 also provides embryonic source of S1P for S1P1 stimulation. The hemorrhagic phenotypes in gDKO embryos were accompanied by increased angiogenesis and defects of tight junction proteins, indicating that S1P from Mfsd2b and Spns2 is essential for blood vessel integrity and maturation. The various sources of S1P in postnatal stages are yet to be fully understood. Postnatal ablation of S1P synthesis enzymes using Mx1Cre shows that Mx1Cre-sensitive cells provide most of plasma S1P. Interestingly, we showed that compound postnatal deletion of Mfsd2b and Spns2 using Mx1Cre (ctDKO-Mx1Cre) resulted in maximal reduction of 80% plasma S1P. Thus, a small amount of plasma S1P is supplied from other sources independent of Mfsd2b and Spns2. Nevertheless, the vasculature in the lung of ctDKO-Mx1Cre mice was compromised. Furthermore, ctDKO-Mx1Cre mice also exhibited severe susceptibility to anaphylaxis, indicating that S1P from Mfsd2b and Spns2 is indispensable during vascular stress. Together, our results show that Mfsd2b and Spns2 provide a critical source of S1P for embryonic development and they also provide a majority of plasma S1P for vascular homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…Recently, monocytes were reported to provide S1P in lymph nodes in response to inflammation (Baeyens et al, 2021). We explored the possibility that the novel source of S1P is released from myeloid cells.…”

Section: Additional Source Of Plasma S1p From Mx1cre-sensitive Cells May Exist Independent Ofmentioning

confidence: 99%

Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and protection of anaphylaxis

Nguyen

Yen

et al. 2021

Preprint

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“…A small trial of fingolimod was initiated with the aim of assessing whether sequestration of lymphocytes via S1PR1 antagonism could reduce postchemoradiation lymphopenia in glioblastoma patients, but have not yet been published (NCT02490930). Interestingly, Baeyens et al recently found that monocytes in the lymph node may also produce S1P and influence T cell differentiation and T cell residence time in the lymph node (152). Their work suggests an alternative mechanism by which drugs that target S1P signaling can influence the glioblastoma TME and immune populations.…”

Section: Altered Phospholipid Metabolismmentioning

confidence: 99%

“…Interestingly, Baeyens et al. recently found that monocytes in the lymph node may also produce S1P and influence T cell differentiation and T cell residence time in the lymph node ( 152 ). Their work suggests an alternative mechanism by which drugs that target S1P signaling can influence the glioblastoma TME and immune populations.…”

Section: Altered Phospholipid Metabolismmentioning

confidence: 99%

Targeting Immunometabolism in Glioblastoma

et al. 2021

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We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.

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“…Recent evidence showed that targeting the S1P/S1PR signaling pathway is crucial for the treatment of immune-mediated diseases (multiple sclerosis and rheumatoid arthritis) [23][24][25], inflammatory bowel diseases [26], lung diseases [27,28], liver diseases [29,30], vascular diseases [31][32][33], brain diseases [34,35], renal diseases [36], and allergy [37]. In the latest clinical trial research, S1P/S1PR also act as a potential new adjuvant therapy to alleviate viral infection of COVID-19 symptoms [38].…”

Section: Introductionmentioning

confidence: 99%

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

Hutami

Izawa

Khurel‐Ochir

et al. 2021

IJMS

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Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.

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Monocyte-derived S1P in the lymph node regulates immune responses

Cited by 51 publications

References 37 publications

Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and protection of anaphylaxis

Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and protection of anaphylaxis

Targeting Immunometabolism in Glioblastoma

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

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