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Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients

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Abstract

Fingolimod (FTY), a second-line oral drug approved for relapsing remitting Multiple Sclerosis (RRMS) acts in preventing lymphocyte migration outside lymph nodes; moreover, several lines of evidence suggest that it also inhibits myeloid cell activation. In this study, we investigated the transcriptional changes induced by FTY in monocytes in order to better elucidate its mechanism of action. CD14+ monocytes were collected from 24 RRMS patients sampled at baseline and after 6 months of treatment and RNA profiles were obtained through next-generation sequencing. We conducted pathway and sub-paths analysis, followed by centrality analysis of cell-specific interactomes on differentially expressed genes (DEGs). We investigated also the predictive role of baseline monocyte transcription profile in influencing the response to FTY therapy. We observed a marked down-regulation effect (60 down-regulated vs. 0 up-regulated genes). Most of the down-regulated DEGs resulted related with monocyte activation and migration like IL7R, CCR7 and the Wnt signaling mediators LEF1 and TCF7. The involvement of Wnt signaling was also confirmed by subpaths analyses. Furthermore, pathway and network analyses showed an involvement of processes related to immune function and cell migration. Baseline transcriptional profile of the HLA class II gene HLA-DQA1 and HLA-DPA1 were associated with evidence of disease activity after 2 years of treatment. Our data support the evidence that FTY induces major transcriptional changes in monocytes, mainly regarding genes involved in cell trafficking and immune cell activation. The baseline transcriptional levels of genes associated with antigen presenting function were associated with disease activity after 2 years of FTY treatment.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

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Acknowledgements

We wish to thank all the patients, family members and nurses of the San Raffaele Hospital MS centre that participated in the study.

Funding

The study was supported by a grant from Fondazione Italiana Sclerosi Multipla (grant number FISM2013/R/13).

Author information

Authors and Affiliations

  1. Department of Neurology, IRCCS San Raffaele Scientific Institute, Via Olgettina, 48, 20132, Milan, Italy

    G. Sferruzza, L. Ferrè, L. Moiola, V. Martinelli, G. Comi, M. Filippi & Federica Esposito

  2. Neuroimmunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    G. Sferruzza & L. Ottoboni

  3. Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit & INSPE, IRCCS San Raffaele Scientific Institute, Milan, Italy

    F. Clarelli, E. Mascia, L. Ferrè, M. Sorosina, S. Santoro & Federica Esposito

  4. Department of Neurology and Multiple Sclerosis Research Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy

    F. Martinelli Boneschi

  5. Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

    F. Martinelli Boneschi

  6. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    M. Filippi

  7. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy

    P. Provero

  8. Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy

    P. Provero

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  1. G. Sferruzza
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Contributions

GS contributed to the clinical characterization of studied patients, performed pathway analyses, contributed to the interpretation of the results and wrote the manuscript. FC contributed to study design, carried out bioinformatic analyses and wrote the manuscript. EM carried out cell separation and the RNASeq experiments and contributed to the interpretation of the results. LF enrolled the patients involved in the study and contributed to the interpretation of the results. LO, MS, SS contributed to the interpretation of the results. LM, VM, GC, MF and FMB contributed to patient enrollment and discussion of article content. PP carried out the bioinformatic and differential expression analyses and contributed the discussion of results. FE designed the experiments, contributed to the discussion of results and wrote the manuscript.

Corresponding author

Correspondence to Federica Esposito.

Ethics declarations

Ethics Approval and Consent to Participate

The local independent Ethical Committee approved the study protocol and all patients signed the informed consent before enrolling in the study.

Consent for Publication

Not applicable.

Competing Interests

G. Sferruzza, F. Clarelli, E. Mascia, L. Ferrè, L. Ottoboni, M. Sorosina, S. Santoro, P. Provero report no competing financial interest.

L. Moiola received honoraria for speaking or partecipating to advisory board from TEVA, Novartis, Biogen, Sanofi e Roche.

V. Martinelli has received honoraria for consulting services or speaking activity from Biogen, Merck, Novartis, TEVA, Almirall, and Genzyme.

G. Comi has received G. Comi has received personal compensation for consulting and speaking activities from Novartis, Teva, Sanofi Genzyme, Merck, Biogen, Roche, Almirall, Celgene, Forward Pharma, Medday and Excemed.

F. Martinelli Boneschi has received compensation for activities with Teva Neuroscience, Biogen Idec, Merck Serono as speaker and/or advisor.

M Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

F. Esposito received honoraria from Novartis and received research support from the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and European Union (Horizon 2020 Research and Innovation programme).

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G. Sferruzza and F. Clarelli contributed equally to the study.

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Sferruzza, G., Clarelli, F., Mascia, E. et al. Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients. Mol Neurobiol 58, 4816–4827 (2021). https://doi.org/10.1007/s12035-021-02465-z

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