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Kidney VISTA prevents IFN-γ/IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury.

ABSTRACT: Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir-/-) kidney suffered more damage than those in WT kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased and the immunometabolic features of T cells changed to showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir-/- parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.

SUBMITTER: Kim MG

PROVIDER: S-EPMC8718152 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

Project description:Backgrounds: The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, has a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. Methods: Wild-type (WT) and VISTA-deficient (Vsir-/-, KO) mice were treated with nephrotoxic serum to induced acute antibody-mediated glomerulonephritis, and their cytokine and fibrosis profiles were compared. Results: VISTA was highly expressed in kidney macrophages (resident more than infiltrating subset). If VISTA was depleted, tubules suffered further damage after glomerular injury. In damaged Vsir–/– mice, the contact frequency of macrophages with infiltrated T cells increased, and then the immunometabolic characteristics of T cells changed to overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu as more producing interleukin-9, which augmented tubulointerstitial fibrosis and irreversible kidney dysfunction. The blocking antibodies against interferon-γ and interleukin-9 protected above pathological process by VISTA depletion. Conclusions: VISTA is a sentinel protein of kidney macrophages, which prevents tubulointerstitial fibrosis via interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.

2021-08-04 | GSE181163 | GEO

Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

Project description:Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

| PRJNA750914 | ENA

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

Project description:Rationale & objectiveTubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy.Study designCross-sectional.Settings & participantsThe Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications.ExposuresSemiquantitative score of IFTA reported by 2 trained pathologists.OutcomesWe measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria.ResultsAmong 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m2, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend).LimitationsSingle time point and spot measures of secretory solutes.ConclusionsGreater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

| S-EPMC8973399 | biostudies-literature

IL-17 Receptor Signaling Negatively Regulates the Development of Tubulointerstitial Fibrosis in the Kidney.

Project description:Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice (Il17ra-/- ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in Il17ra -/- mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, Il17ra-/- mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases.

| S-EPMC6204168 | biostudies-literature

Platelet-derived growth factors (PDGFs) in glomerular and tubulointerstitial fibrosis.

Project description:Renal fibrosis is the hallmark of chronic kidney disease progression and is characterized by an exaggerated wound-healing process with the production of renal scar tissue. It comprises both the glomerular and the tubulointerstitial compartments. Among the factors that contribute to kidney fibrosis, the members of the platelet-derived growth factor (PDGF) family are among the best characterized ones. They appear to be the key factors in driving renal fibrosis, independent of the underlying kidney disease. The PDGF family consists of four isoforms (PDGF-A, -B, -C, and -D) and two receptor chains (PDGFR-α and -β), which are constitutively or inducibly expressed in most renal cells. These components have an irreplaceable role in kidney development by recruitment of mesenchymal cells to the glomerular and tubulointerstitial compartments. They further regulate multiple pathophysiologic processes including cell proliferation, cell migration, expression and accumulation of extracellular matrix, production and secretion of pro- and anti-inflammatory mediators, vascular permeability, and hemodynamics. This review provides a brief update on the role of different PDGF isoforms in the development of glomerulosclerosis and tubulointerstitial fibrosis, newly identified endogeneous PDGF antagonists, and resulting potential therapies.

| S-EPMC4536969 | biostudies-other

Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis.

Project description:V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir -/- mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir -/- CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation. Enhanced TLR7 signaling in Vsir -/- dendritic cells (DCs) led to the hyper-activation of Erk1/2 and Jnk1/2, and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRγδ+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27- γδ T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27- γδ T cells were expanded in the Vsir -/- mice and amplified the inflammatory cascade. In conclusion, this study has demonstrated that VISTA critically regulates the inflammatory responses mediated by DCs and IL-17-producing TCRγδ+ and CD4+ Th17 T cells following TLR7 stimulation. Our finding provides a rationale for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune and inflammatory disorders.

| S-EPMC5431161 | biostudies-literature

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney.

Project description:IL-36α, a member of the IL-1 family, is a crucial mediator of inflammatory responses. We previously found that IL-36α was overexpressed in injured distal tubules (DTs); however, its pathological function remains unclear. Herein, unilateral ureter obstruction (UUO) or folic acid (FA) injection was performed in mouse kidneys to assess the role of IL-36α in kidney injury. IL-36α mRNA and protein expression significantly increased in the kidneys within 24 h after UUO. IL-36α localized to dilated DTs. IL-36α expression significantly correlated with the progression of tubulointerstitial cell infiltration and tubular epithelium cell death in UUO kidneys and with renal dysfunction in FA-induced acute kidney injury mice. At 24 h after UUO, IL-36α+ DT epithelial cells showed loose intercellular digitations. IL-1RL2, an IL-36α receptor protein, localized to podocytes, proximal tubules, and DTs in the healthy kidney. IL-1RL2 was expressed in interstitial cells and platelets or extended primary cilia of DT epithelial cells in UUO kidneys. IL-36α stimulation promoted the production of IL-6 and Prss35, an inflammatory cytokine and collagen remodeling-associated enzyme, respectively, in cultured NIH3T3 fibroblasts. UUO-treated IL-36α-knockout (KO) mice showed milder kidney injury features than wild-type (WT) mice did. In UUO kidneys from IL-36α-KO mice, the expression of genes associated with inflammatory response and sensory perception was significantly different from that in WT mice. Altogether, our data indicate an association between intrarenal IL-36α overexpression and the progression of tubulointerstitial inflammations and morpho-functional alterations of DT epithelial cells. IL-36α may be a novel kidney injury marker useful for evaluating DT damages.

| S-EPMC5660075 | biostudies-literature

Plk1 promotes renal tubulointerstitial fibrosis by targeting autophagy/lysosome axis.

Project description:The prevalence of chronic kidney disease (CKD) has been increasing over the past decades. However, no effective therapies are available for delaying or curing CKD. Progressive fibrosis is the major pathological feature of CKD, which leads to end-stage renal disease (ESRD). The present study showed that Polo-like kinase 1 (Plk1) was upregulated in the kidneys of CKD patients and mice subjected to unilateral ureteral obstruction (UUO) with location in proximal tubules and tubulointerstitial fibroblasts. Pharmacological inhibition, genetic silencing or knockout of Plk1 attenuated obstructive nephropathy due to suppressed fibroblast activation mediated by reduced autophagic flux. We found Plk1 plays a critical role in maintaining intralysosomal pH by regulating ATP6V1A phosphorylation, and inhibition of Plk1 impaired lysosomal function leading to blockade of autophagic flux. In addition, Plk1 also prevented partial epithelial-mesenchymal transition (pEMT) of tubular epithelial cells via autophagy pathway. In conclusion, this study demonstrated that Plk1 plays a pathogenic role in renal tubulointerstitial fibrosis by regulating autophagy/lysosome axis. Thus, targeting Plk1 could be a promising strategy for CKD treatment.

| S-EPMC10462727 | biostudies-literature

NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ-IL-27 axis.

Project description:IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ(-/-) mice repleted with IFN-γ +/+: NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC-dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10-producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ-IL-27 axis.

| S-EPMC4577839 | biostudies-literature

Analysis of IL-12 p40 subunit gene and IFN-gamma G5644A polymorphisms in Idiopathic Pulmonary Fibrosis.

Project description:BackgroundGenes encoding cytokine mediators are prime candidates for genetic analysis in conditions with T-helper (Th) cell disease driven imbalance. Idiopathic Pulmonary Fibrosis (IPF) is a predominantly Th2 mediated disease associated with a paucity of interferon-gamma (IFN-gamma). The paucity of IFN-gamma may favor the development of progressive fibrosis in IPF. Interleukin-12 (IL-12) plays a key role in inducing IFN-gamma production. The aim of the current study was to assess whether the 1188 (A/C) 3'UTR single nucleotide polymorphism (SNP) in the IL-12 p40 subunit gene which was recently found to be functional and the 5644 (G/A) 3' UTR SNP of the IFN-gamma gene were associated with susceptibility to IPF.MethodsWe investigated the allelic distribution in these loci in UK white Caucasoid subjects comprising 73 patients with IPF and 157 healthy controls. The SNPs were determined using the polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3'-end.ResultsOur results showed that these polymorphisms were distributed similarly in the IPF and control groupsConclusionWe conclude that these two potentially important candidate gene single nucleotide polymorphisms are not associated with susceptibility to IPF.

| S-EPMC185252 | biostudies-literature

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