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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1461841
This article is part of the Research Topic NETosis, Complement Activation and Pattern Recognition at the Intersection of Inflammatory Disorders View all 5 articles

Dexamethasone and IFN-γ primed mesenchymal stem cells conditioned media immunomodulates aberrant NETosis in SLE via PGE2 and IDO

Provisionally accepted
Khushbu Priya Khushbu Priya 1Hiral Thacker Hiral Thacker 1Manaswi Chaubey Manaswi Chaubey 2Madhukar Rai Madhukar Rai 2Shambhavi Singh Shambhavi Singh 3Sonali Rawat Sonali Rawat 4Kiran Giri Kiran Giri 5Sujata Mohanty Sujata Mohanty 4Geeta Rai Geeta Rai 1*
  • 1 Molecular and Human Genetics, Faculty of Science, Banaras Hindu University, Varanasi, India
  • 2 Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
  • 3 Padmashree Dr. D.Y. Patil University, Navi Mumbai, Maharashtra, India
  • 4 Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
  • 5 Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-, India

The final, formatted version of the article will be published soon.

    Background: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology.Objective: To investigate the immunomodulatory effects of Dexamethasone-primed Wharton's jelly (WJ) derived MSCs CM (DW) and IFN-γ-primed WJ-MSCs-CM (IW) on NETosis and associated protein markers in SLE patients' LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein.Methods: We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing ex vivo and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β).Results: Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs.Conclusion: Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment.

    Keywords: NEtosis, neutrophil extracellular trap formation, systemic lupus erythematosus, Reactive Oxygen Species, Hydroxychloroquine, ribonucleoprotein immune complexes, lupus model

    Received: 09 Jul 2024; Accepted: 09 Oct 2024.

    Copyright: © 2024 Priya, Thacker, Chaubey, Rai, Singh, Rawat, Giri, Mohanty and Rai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Geeta Rai, Molecular and Human Genetics, Faculty of Science, Banaras Hindu University, Varanasi, India

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.