Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients
Samantha Slight-Webb, Joel M. Guthridge, Eliza F. Chakravarty, Hua Chen, Rufei Lu, Susan Macwana, Krista Bean, Holden T. Maecker, Paul J. Utz, Judith A. James
Samantha Slight-Webb, Joel M. Guthridge, Eliza F. Chakravarty, Hua Chen, Rufei Lu, Susan Macwana, Krista Bean, Holden T. Maecker, Paul J. Utz, Judith A. James
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Research Article Immunology

Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients

Abstract

Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF–) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4+ Th17-type and CD4+ Treg-type cells, compared with MMF– patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.

Authors

Samantha Slight-Webb, Joel M. Guthridge, Eliza F. Chakravarty, Hua Chen, Rufei Lu, Susan Macwana, Krista Bean, Holden T. Maecker, Paul J. Utz, Judith A. James

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Figure 3

Cell subset marker expression reveals activated B cell, T cell, and DC subsets, and elevated CCR6 expression in MMF+ SLE patients.

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Cell subset marker expression reveals activated B cell, T cell, and DC s...
All 55 cell subsets as determined by manual gating were assessed for frequencies of activating, inhibitory, and chemokine receptors. Significant differences in cell surface marker expression are highlighted in MMF– (n = 10) and MMF+ SLE patients’ (n = 5) (A) naive B cells (CD38), (B) naive B cells (CD86), (C) naive B cells (CCR6), (E) memory B cells (CD86), and (F) plasmablasts (CCR6). Nonsignificant differences were found in expression on double-negative B cells of (G) CCR6, (H) CD38, and (I) CD86. Significant differences in expression were also found in (J) T cells (CCR6), (K) CD8+ memory T cells (CCR6), (L) CD4+ T cells (CD38), and (M) CXCR3+ DCs (CD38). Concatenated files of MMF– patients (n = 10) and MMF+ patients (n = 5) were used to create t-SNE dot plots individually colored by channel using arcsinh(5)-transformed expression values for (D) CD38 and CCR6. Cell orientations for the t-SNE plots in D can be found in Figure 1. *P < 0.05, **P < 0.01 by Kruskal-Wallis test with Dunn’s multiple comparisons test. Median ± standard deviation shown.