Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis

Ghali, Joanna R.; O’Sullivan, Kim M.; Eggenhuizen, Peter J.; Holdsworth, Stephen R.; Kitching, A. Richard

doi:10.1159/000453059

Cited by 11 publications

(10 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years IL-17A and, to lesser degree, IL-17F and IL-17RA have been identified as important proinflammatory regulators and potential therapeutic targets in autoimmune and inflammatory kidney diseases, including human and experimental crescentic GN. [6][7][8][25][26][27][28] However, the potential function of other IL-17 cytokines and IL-17 receptors is still unclear. We measured serum protein levels of the IL-17 cytokine family members in 70 patients with ANCA-associated GN, the most common form of crescentic GN.…”

Section: Discussionmentioning

confidence: 99%

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

Krohn¹,

Nies²,

Kapffer³

et al. 2018

JASN

View full text Add to dashboard Cite

The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced T17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4 T17 cells, and loss of this expression prevented the T17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes T17 cell responses and immune-mediated kidney disease IL-17RE expressed on CD4 T17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for T17-induced autoimmune disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

Krohn¹,

Nies²,

Kapffer³

et al. 2018

JASN

View full text Add to dashboard Cite

show abstract

“…The Th17/IL-17 axis participates in the production of autoantibodies by B cells, as demonstrated in studies with autoimmune models in which the IL-17 drives the development of autoreactive germinal center (GC); and mice lacking the IL-17 receptor have reduced B cell development and humoral responses (229,230). In another study with an autoimmune disease model, the blockade of IL-17 signaling was associated with a significant reduction in both the number and size of germinal centers (231).…”

Section: Production Of Autoantibodiesmentioning

confidence: 99%

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a disease characterized by dysregulation and hyperreactivity of the immune response at various levels, including hyperactivation of effector cell subtypes, autoantibodies production, immune complex formation, and deposition in tissues. The consequences of hyperreactivity to the self are systemic and local inflammation and tissue damage in multiple organs. Lupus nephritis (LN) is one of the most worrying manifestations of SLE, and most patients have this involvement at some point in the course of the disease. Among the effector cells involved, the Th17, a subtype of T helper cells (CD4+), has shown significant hyperactivation and participates in kidney damage and many other organs. Th17 cells have IL-17A and IL-17F as main cytokines with receptors expressed in most renal cells, being involved in the activation of many proinflammatory and profibrotic pathways. The Th17/IL-17 axis promotes and maintains repetitive tissue damage and maladaptive repair; leading to fibrosis, loss of organ architecture and function. In the podocytes, the Th17/IL-17 axis effects include changes of the cytoskeleton with increased motility, decreased expression of health proteins, increased oxidative stress, and activation of the inflammasome and caspases resulting in podocytes apoptosis. In renal tubular epithelial cells, the Th17/IL-17 axis promotes the activation of profibrotic pathways such as increased TGF-β expression and epithelial-mesenchymal transition (EMT) with consequent increase of extracellular matrix proteins. In addition, the IL-17 promotes a proinflammatory environment by stimulating the synthesis of inflammatory cytokines by intrinsic renal cells and immune cells, and the synthesis of growth factors and chemokines, which together result in granulopoiesis/myelopoiesis, and further recruitment of immune cells to the kidney. The purpose of this work is to present the prognostic and immunopathologic role of the Th17/IL-17 axis in Kidney diseases, with a special focus on LN, including its exploration as a potential immunotherapeutic target in this complication.

show abstract

“…76 IL-17 seems to be involved in autoimmune glomerulonephritis. 77,78 It has been suggested that IL-17R-knockout mice were protected from crescent formation but not from glomerular necrosis or renal interstitial injury. 77,78 The role of other IL-17 cytokine family members and their receptors in inflammatory nephropathies remains unclear.…”

Section: Il-17mentioning

confidence: 99%

IL-12 and IL-23/Th17 axis in systemic lupus erythematosus

Larosa

Zen

Gatto

et al. 2019

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a very complex disease where multiple immunological pathways can concur in inducing tissue damage. Cytokines are key mediators in this process and among them the role of interleukin (IL)-12 and the IL-23/Th17 axis has recently emerged. IL-12 and IL-23 have a heterodimeric structure with a common subunit, named p40. Although they share a partially common structure, their functions appear slightly different. Indeed, IL-12 is a key cytokine in inducing an efficient T helper 1 (Th1) response and in Th differentiation, while IL-23 plays a crucial role in chronic inflammation and Th17 cell activation, which results in IL-17 secretion. The increasing knowledge on the interaction between IL-12 and IL-23/Th17 axis in the development of autoimmune diseases has led to the identification of new therapeutic strategies targeting these immunological pathways. IL-23/Th17 axis has recently been suggested to be essential in developing lupus nephritis, both in mice and in humans. In keeping with these observations, ustekinumab, a fully human IgG1κ monoclonal antibody (mAb) directed towards p40 subunit, has been investigated in SLE. Promising data from a phase II randomized controlled trial in SLE patients suggest that this mAb might be a potential novel therapeutic strategy in SLE. In this review, we summarize the complex interaction between IL-12 and IL-23/Th17 axis in SLE with a special focus on drugs which affect this immune pathway. Impact statement Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.

show abstract

Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis

Cited by 11 publications

References 83 publications

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

IL-12 and IL-23/Th17 axis in systemic lupus erythematosus

Contact Info

Product

Resources

About