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The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus

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Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with a broad spectrum of clinical presentations and association with multiple immunological abnormalities. Recent research of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) signaling pathway—revealed aberrant STAT signaling in inflammatory conditions and autoimmune diseases including SLE. STAT proteins are major components in interferon (IFN)-dependent gene expression and are responsible for signal transduction of over 50 cytokines, hormones, and growth factors regulating key cellular processes such as survival, proliferation, and differentiation. This review summarizes the present evidence from experimental animal models and patients with SLE for the involvement of STAT pathways in the pathogenesis of SLE underlining the role of different members of the STAT family. Genome-wide association studies provided evidence that variations in STAT4 gene are linked to the development of SLE in humans. First integration with genome-wide epigenomics data suggests that control of CD4+ T cell differentiation in which STATs play a major role may be an important component of the genetic contribution to disease susceptibility. Increased transcript and total protein STAT1 levels were described both in SLE T and B cells suggestive of the priming mechanisms that augment STAT1 signaling responses to IFN. STAT3 has a crucial role in Th17 differentiation, T follicular helper, and B cells, and STAT3 inhibition could represent a possible future therapeutic target in SLE. STAT5B appears to act as a critical modulator of human Treg development and function. While the imbalance between phosphorylated STAT5 and STAT3 in human SLE T cells was implicated in dysregulated IL-10 expression, Treg-specific deletion of STAT3 in mouse model even enhanced Th17-mediated inflammation. Finally, we present also a comprehensive analysis of studies investigating STAT signaling responses in conventional and regulatory subsets of SLE T and B cells and possible implications of STAT inhibition for clinical therapy.

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Acknowledgments

This work was partially supported by the University Medical Center Ljubljana Research Grant 20140208.

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Authors and Affiliations

  1. Department of Laboratory Diagnostics, University Medical Center Maribor, Maribor, Slovenia

    Aleš Goropevšek

  2. Faculty of Medicine, University of Maribor, Maribor, Slovenia

    Aleš Goropevšek

  3. Department of Allergology, Rheumatology and Clinical Immunology, University Children’s Hospital, University Medical Center Ljubljana, Bohoričeva 20, SI-1525, Ljubljana, Slovenia

    Marija Holcar & Tadej Avčin

  4. Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    Tadej Avčin

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  1. Aleš Goropevšek
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Correspondence to Tadej Avčin.

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Goropevšek, A., Holcar, M. & Avčin, T. The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus. Clinic Rev Allerg Immunol 52, 164–181 (2017). https://doi.org/10.1007/s12016-016-8550-y

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