Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Syed, Shahzad N.; Raue, Rebecca; Weigert, Andreas; Knethen, Andreas von; Brüne, Bernhard

doi:10.3390/cells8080785

Cited by 18 publications

(27 citation statements)

References 65 publications

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“…Finally, to understand the clinical relevance of our finding, we analyzed expression pattern of these genes in an inflammatory condition and a cancer type where both S1P and macrophages have been reported in poor prognosis [ 43 , 44 , 45 , 46 ]. We analyzed publicly available datasets of patients comprising 535 tumor samples and 72 control tissue of clear cell renal cell carcinoma [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

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Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

Syed

Weigert

Brüne

2020

IJMS

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Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.

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Section: Resultsmentioning

confidence: 99%

“…S1pr1 KO ( S1pr1 fl/fl Lyz2 Cre/Cre ) and corresponding WT ( S1pr1 fl/fl Lyz2 Cre/wt ) on C57BL/6 background have been described before [ 46 ]. Sphk1 KO [ 95 , 96 ] and Sphk2 KO [ 12 , 97 ] from Novartis were described before and were backcrossed for at least 10 generations into a C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

Syed

Weigert

Brüne

2020

IJMS

Self Cite

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“…We previously reported that increased expression of S1PR2 is closely related to the disruption of vascular endothelial cell barrier and angiogenesis, but inhibition of S1PR2 expression can reverse the vascular endothelial cell injury 18 . In line with this finding, more studies support the involvement of S1PRs in the regulation of vascular endothelial cell barrier function, vascular density and leucocyte migration across vascular endothelium within inflame tissues 19,20 . However, little is known about the special importance of S1PRs in the intestinal vascular changes in IBD.…”

Section: Introductionmentioning

confidence: 72%

“…In the mouse chronic IBD model, the expression of S1PR1 was also increased in intestinal submucosa and muscular microvessels 51 . Further studies have shown that there is a significant change in vascular density in the inflamed tissues of myeloid S1PR1 knockout mice 52 . Additionally, S1PR2 is another important driver of pathological angiogenesis in the process of inflammation, and S1PR2 antagonists can reverse the increase in vascular density caused by inflammation 53 .…”

Section: S1prs and Intestinal Angiogenesis In Ibdmentioning

confidence: 99%

Role of sphingosine‐1‐phosphate receptors in vascular injury of inflammatory bowel disease

Wang

Chen

Xiang

et al. 2021

J Cellular Molecular Medi

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Sphingosine‐1‐phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR‐targeted therapies.

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“…Dermal macrophages, activated by cytokines released from T cells or DCs, produce large amounts of TNF-α, IL-12 and IL-23 in response to local S1P, leading to the skin changes observed in psoriasis. TNF-α signalling is orchestrated by intracellular S1P through targeting TNF receptor-associated factor 2 [115][116][117][118]. Moreover, S1P acts as a chemoattractant for monocytes, which further polarise into macrophages.…”

Section: Sphingolipid Action In Inflammation-focus On the Molecular Mmentioning

confidence: 99%

Unbalanced Sphingolipid Metabolism and Its Implications for the Pathogenesis of Psoriasis

Bocheńska

Gabig-Cimińska

2020

Molecules

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Sphingolipids (SLs), which have structural and biological responsibilities in the human epidermis, are importantly involved in the maintenance of the skin barrier and regulate cellular processes, such as the proliferation, differentiation and apoptosis of keratinocytes (KCs). As many dermatologic diseases, including psoriasis (PsO), intricately characterized by perturbations in these cellular processes, are associated with altered composition and unbalanced metabolism of epidermal SLs, more education to precisely determine the role of SLs, especially in the pathogenesis of skin disorders, is needed. PsO is caused by a complex interplay between skin barrier disruption, immune dysregulation, host genetics and environmental triggers. The contribution of particular cellular compartments and organelles in SL metabolism, a process related to dysfunction of lysosomes in PsO, seems to have a significant impact on lysosomal signalling linked to a modulation of the immune-mediated inflammation accompanying this dermatosis and is not fully understood. It is also worth noting that a prominent skin disorder, such as PsO, has diminished levels of the main epidermal SL ceramide (Cer), reflecting altered SL metabolism, that may contribute not only to pathogenesis but also to disease severity and/or progression. This review provides a brief synopsis of the implications of SLs in PsO, aims to elucidate the roles of these molecules in complex cellular processes deregulated in diseased skin tissue and highlights the need for increased research in the field. The significance of SLs as structural and signalling molecules and their actions in inflammation, in which these components are factors responsible for vascular endothelium abnormalities in the development of PsO, are discussed.

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Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation

Cited by 18 publications

References 65 publications

Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

Role of sphingosine‐1‐phosphate receptors in vascular injury of inflammatory bowel disease

Unbalanced Sphingolipid Metabolism and Its Implications for the Pathogenesis of Psoriasis

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