Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent
Abstract
:1. JAK/STAT Pathway and Autoimmunity: An Overview
1.1. Physiology and Pathophysiology
1.2. JAK/STAT System: Balancing between Autoimmunity and Immune Deficiency
2. The JAK/STAT Pathway in Rheumatic Diseases
3. The JAK/STAT Pathway in Experimental SLE
3.1. Evidence from In Vitro Studies
3.2. Evidence from In Vivo Studies
3.2.1. Lupus Nephritis
3.2.2. Cutaneous Lupus
3.2.3. Serology and Autoantibodies
3.2.4. Lupus-Associated Vascular Dysfunction
4. From Bench to Bedside: Data from Clinical Trials and Future Perspectives
5. Conclusions and Perspectives
Funding
Conflicts of Interest
References
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JAK/STAT Member | Proteins Signaling through Each JAK/STAT Member | Proposed Effect of Therapeutic Inhibition (Simplified) |
---|---|---|
JAK1 | Interferons (α, β, γ), IL-2, IL-4, IL-6 family cytokines, IL-7, IL-9, IL-10 family cytokines | Immunosuppression |
JAK2 | EPO, TPO, GM-CSF, G-CSF, IL-3, IL-5, interferon-γ, GH, leptin | Immunosuppression, inhibition of hematopoietic cell differentiation |
JAK3 | IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 | Immunosuppression |
TYK2 | Interferons (α, β, γ), IL-12, IL-23 | Immunosuppression |
STAT1 | Interferons (α, β, γ) | Immunosuppression |
STAT2 | Interferons α and β | Immunosuppression |
STAT3 | IL-6 family cytokines, IL-10 family cytokines, G-CSF, leptin, IL-21, IL-27, several oncogenes and growth factors | Immunosuppression, inhibition of hematopoietic cell differentiation |
STAT4 | Interferons α and β, IL-12, IL-23 | Immunosuppression, inhibition of Th1 cell differentiation |
STAT5 | GM-CSF, GH, TPO, EPO, IL-2, IL-3, IL-5, IL-7, IL-9, IL-15 | Immunosuppression, inhibition of hematopoietic cell differentiation |
STAT6 | IL-4, IL-13 | Immunosuppression, inhibition of Th2 cell differentiation |
Target | Type of Mutation | Phenotype | Ref |
---|---|---|---|
JAK3 | Loss-of-function | Severe combined immune deficiency (SCID) | [14] |
STAT1 and STAT2 | Loss-of-function | Immunodeficiency | [15] |
STAT5 | Loss-of-function | Immunodeficiency or autoimmunity | |
STAT3 | Gain-of-function | Early-onset lymphoproliferative disease and autoimmunity | [16] |
STAT1 | Gain-of-function | Chronic mucocutaneous candidiasis and autoimmunity | [17] |
STAT3 | Dominant negative mutations | Hyper-IgE syndrome | [18] |
Different STATs | Polymorphisms | Susceptibility for systemic autoimmune diseases | [19,20] |
Study [ref.] | Compound | Main Molecular Target | Mouse Model | Design | Main Effects |
---|---|---|---|---|---|
Wang et al. [42] | AG-490 | JAK2 | MRL/lpr | P | ↓ nephritis, ↓ sialadenitis, ↓ serum dsDNA antibodies |
Lu et al. [43] | CEP-33779 | JAK2 | MRL/lpr, BWF1 | P (MRL/lpr), E (BWF1) | P: ↓ nephritis, ↓ splenomegaly, ↓ lymphadenopathy, ↑ serum C3 levels; E: ↓ nephritis, ↑ survival, ↓ level of long-living plasma cells in the spleen and bone marrow; Both (serum): ↓ ANA, ↓ anti-dsDNA and ↓ anti-Smith antibodies |
Ripoll et al. [44] | Tofacitinib | JAK3 and JAK1 | NZB/NZWF1 | E | ↓ nephritis, ↑ survival, ↓ serum anti-dsDNA antibodies |
Ikeda et al. [45] | Tofacitinib | JAK3 and JAK1 | NZB/NZWF1, MRL | P | ↓ nephritis, ↓ serum anti-dsDNA antibodies |
Furumoto et al. [46] | Tofacitinib | JAK3 and JAK1 | MRL/lpr | P, E | ↓ nephritis, ↓ skin lesions, ↓ serum anti-dsDNA antibodies, ↓ ANA, ↓ vascular dysfunction |
Wu et al. [47] | CDDO-Me | JAK1 and STAT3 | B6-Sle1.Sle3, MRL/lpr, NZM2410 | P (B6-Sle1.Sle3, MRL/lpr), E (NZM2410) | ↓ nephritis, ↓ serum anti-dsDNA antibodies |
Edwards et al. [48] | Stattic | STAT3 | MRL/lpr | P | ↓ nephritis, ↓ serum anti-dsDNA antibodies, ↑ serum C3 levels |
Du et al. [49] | Stattic | STAT3 | MRL/lpr | P | ↓ renal tubulointerstitial lesions |
Chan et al. [50] | Ruxolitinib | JAK1 and JAK2 | MRL/lpr | E | ↓ skin lesions |
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Alunno, A.; Padjen, I.; Fanouriakis, A.; Boumpas, D.T. Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent. Cells 2019, 8, 898. https://doi.org/10.3390/cells8080898
Alunno A, Padjen I, Fanouriakis A, Boumpas DT. Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent. Cells. 2019; 8(8):898. https://doi.org/10.3390/cells8080898
Chicago/Turabian StyleAlunno, Alessia, Ivan Padjen, Antonis Fanouriakis, and Dimitrios T. Boumpas. 2019. "Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent" Cells 8, no. 8: 898. https://doi.org/10.3390/cells8080898