Rationale for Use of Sphingosine-1-Phosphate Receptor Modulators in COVID-19 Patients: Overview of Scientific Evidence

Abstract

Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.

Keywords: cytokine suppression; fingolimod; immune response; siponimod.

FIG. 1.

Innate immune response and adaptive immune responses of CoV during an infection (Bergmann and Silverman ; Hejrati and others ; Trougakos and others 2021). ACE, angiotensin-converting enzyme; ANG, angiotensin; ARDS, acute respiratory distress syndrome; CoV, coronaviruses; IL, interleukin; IRF, interferon regulatory factors; NF-κβ, nuclear factor kappa B.

FIG. 2.

Suppressed cytokine secretion by fingolimod via PP2A activation. The PP2A activator fingolimod overcomes OA-mediated inhibition of basal PP2A phosphatase activity and significantly represses IL-6 and IL-8 mRNA expression and cytokine secretion. A549 cells were treated for 6 h with 2.5 μM fingolimod before 45 min with 1 μM OA, compared with vehicle. IL-6 and IL-8 protein secretion measured at 24 h. *Denotes a significant effect of OA and §for fingolimod (P < 0.05). Data are mean + SEM values from three independent experiments. Figure adapted from Rahman and others (2015). mRNA, messenger RNA; OA, okadaic acid; PP2A, protein phosphatase 2A; SEM, standard error of mean. Reproduced under Creative Commons Attribution 4.0 International License from Rahman MM, Rumzhum NN, Morris JC, Clark AR, Verrills NM, Ammit AJ. Scientific Report 2015 May 18;5:10063; DOI: 10.1038/srep10063.

FIG. 3.

Barrier enhancement by fingolimod via c-Abl tyrosine kinase. Left panel: HPAEC were transfected with 100 nM c-Abl or control siRNA and seeded onto Transwell inserts. After FTY720 stimulation (1 μM), FITC-dextran was added into the top chamber and incubated for 2 h. The fluorescent intensity of the bottom chamber was analyzed by fluorometry as per Methods. n = 4. *P < 0.031 versus control siRNA. Right panel: HPAEC were preincubated for 1 h with the c-Abl inhibitor, AG957 (20 μM), or vehicle control and then stimulated with FTY720 (1 μM) or vehicle. Data are representative of three independent experiments. Figure adapted from Wang and others (2011). AG957, c-Abl inhibitor; Con, control; FITC, fluorescein isothiocyanate; FTY720, fingolimod; HPAEC, human pulmonary artery endothelial cells; siRNA, small interfering RNA. Reproduced with permission of the © ERS 2022. European Respiratory Journal Jul 2011, 38 (1) 78-88; DOI: 10.1183/09031936.00047810. Copyright permission reference number is ERJPM076-2022-23.

FIG 4.

Short-term exposure of S1PR modulators in COVID-19 ARDS: Summary of potential mechanisms. *Differential PK/PD profiles as described elsewhere. Bregs, regulatory B cell; IL, interleukin; PK/PD, pharmacokinetic/pharmacodynamic; PP2A, protein phosphatase 2A; S1P, sphingosine-1-phosphate; Th, helper T cell; Tregs, regulatory T cell.