Development of Th17‐Associated Interstitial Kidney Inflammation in Lupus‐Prone Mice Lacking the Gene Encoding STAT‐1

Yiu, Gloria; Rasmussen, Tue Kruse; Ajami, Bahareh; Haddon, D. James; Chu, Alvina D.; Tangsombatvisit, Stephanie; Haynes, Winston; Diep, Vivian K.; Steinman, Lawrence; Faix, James D.; Utz, Paul J.

doi:10.1002/art.39535

Cited by 9 publications

(6 citation statements)

References 84 publications

(121 reference statements)

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“…In the MRL/lpr mouse model, STAT1 is overexpressed in both B and T cells. STAT1 gene silencing (STAT1 −/− ) in this mouse model is accompanied by a decrease of CD4 + producing IFN-γ T cells, a milder course of nephritis and a remarkable decrease of auto-ab levels (121–123). In humans diagnosed with LE as in mice, STAT1 is overexpressed in T and B cells.…”

Section: Lupus Erythematosusmentioning

confidence: 91%

Emerging Topical and Systemic JAK Inhibitors in Dermatology

2019

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Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.

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Section: Lupus Erythematosusmentioning

confidence: 91%

Emerging Topical and Systemic JAK Inhibitors in Dermatology

2019

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“…MRL/ lpr mice received daily administration of vehicle or tofacitinib (10 mg/kg) for 6 weeks (therapeutic treatment trial) or 8 weeks (preventive treatment trial) by oral gavage (Figure A). The numbers of animals used for experiments were calculated based on previous studies using preventive or therapeutic treatments in murine SLE . Overall, the number of mice ranged from 6 to 14 per group.…”

Section: Methodsmentioning

confidence: 99%

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction

Furumoto

Smith

Blanco

et al. 2016

Arthritis & Rheumatology

192

127

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Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.

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“…These results suggest that STAT1 can be a therapeutic target in SLE. However, the involvement of STAT1 in SLE is complex because STAT1 deficient lupus-prone mice exhibit interstitial kidney inflammation associated with Th17 cells, by shunting to STAT3/4 activation ( 152 ).…”

Section: Cytokine Signalingmentioning

confidence: 99%

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

2018

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Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to “self” leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

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Development of Th17‐Associated Interstitial Kidney Inflammation in Lupus‐Prone Mice Lacking the Gene Encoding STAT‐1

Cited by 9 publications

References 84 publications

Emerging Topical and Systemic JAK Inhibitors in Dermatology

Emerging Topical and Systemic JAK Inhibitors in Dermatology

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

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