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Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing.

ABSTRACT: The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix. The lymphotoxin ? signaling pathway mediates activation of FRCs, and chronic treatment with lymphotoxin ? receptor-immunoglobulin fusion protein (LT?r-Ig) resulted in marked alteration of the KLN as well as augmentation of renal fibrosis. Depletion of FRCs reduced T cell activation in the KLN and ameliorated renal injury in acute IRI. Repetitive renal IRI was associated with senescence of FRCs, fibrosis of the KLN, and renal scarring, which were ameliorated by FRC administration. Therefore, our study emphasizes the critical role of FRCs in both the initiation and repair phases of injury following IRI of the kidney.

SUBMITTER: Maarouf OH

PROVIDER: S-EPMC6124521 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing.

Maarouf Omar H OH Uehara Mayuko M Kasinath Vivek V Solhjou Zhabiz Z Banouni Naima N Bahmani Baharak B Jiang Liwei L Yilmam Osman A OA Guleria Indira I Lovitch Scott B SB Grogan Jane L JL Fiorina Paolo P Sage Peter T PT Bromberg Jonathan S JS McGrath Martina M MM Abdi Reza R

JCI insight 20180712 13

The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significan ...[more]

PMID: 29997302

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Project description:Although the primary organ has been the subject of intense investigation in the field of organ fibrosis over the past several decades, the presence of lymph node fibrosis due to persistent activation of the immune response in its partner organ remains largely unknown. Previously, we demonstrated that activation of the immune response following ischemia-reperfusion injury (IRI) and crescentic glomerulonephritis (CGN) in the kidney was associated with extracellular matrix (ECM) production by fibroblastic reticular cells (FRCs) of the kidney-draining lymph node (KLN). Here, we sought to determine whether FRCs in the KLN become similarly fibrogenic following unilateral ureteral obstruction (UUO) of the kidney. We subjected 6-8-week-old C57BL/6J mice to UUO for 2, 7, and 14 days. We examined the microarchitecture of the kidney and KLN by immunofluorescence staining at each timepoint, and we quantified immune cell populations in the KLN by flow cytometry. The contralateral kidney unaffected by UUO and its partner KLN were used as controls. We found through immunofluorescence staining that FRCs increased production of ECM fibers and remodeled the microarchitecture of the UUO KLN, contributing to fibrosis that mirrored the changes in the kidney. We also observed by flow cytometry that the populations of CD11b+ antigen-presenting cells, CD11c+ dendritic cells, and activated CD4+ and CD8+ T cells were significantly higher in the UUO KLN than the KLN draining the unaffected contralateral kidney. Expression of the TGFβ/TGFβR signaling pathway was upregulated and colocalized with FRCs in the UUO KLNs, suggesting a possible mechanism behind the fibrosis. Both release of ureteral ligation at 2 days following UUO and depletion of FRCs at the time of injury onset halted the progression of fibrosis in both the kidney and the KLN. These findings for the first time highlight the association between fibrosis both in the kidney and the KLN during UUO, and they lay the groundwork for future studies that will investigate more deeply the mechanisms behind the connection between FRCs and KLN fibrosis.

Project description:BACKGROUND:Systemic autoimmunity can be present years before clinical onset of rheumatoid arthritis (RA). Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) regulate immune responses through their intimate connection with leucocytes. We postulate that malfunctioning of LNSCs creates a microenvironment in which normal immune responses are not properly controlled, possibly leading to autoimmune disease. In this study we established an experimental model for studying the functional capacities of human LNSCs during RA development. METHODS:Twenty-four patients with RA, 23 individuals positive for autoantibodies but without clinical disease (RA risk group) and 14 seronegative healthy control subjects underwent ultrasound-guided inguinal lymph node (LN) biopsy. Human LNSCs were isolated and expanded in vitro for functional analyses. In analogous co-cultures consisting of LNSCs and peripheral blood mononuclear cells, ?CD3/?CD28-induced T-cell proliferation was measured using carboxyfluorescein diacetate succinimidyl ester dilution. RESULTS:Fibroblast-like cells expanded from the LN biopsy comprised of fibroblastic reticular cells (gp38+CD31-) and double-negative (gp38-CD31-) cells. Cultured LNSCs stably expressed characteristic adhesion molecules and cytokines. Basal expression of C-X-C motif chemokine ligand 12 (CXCL12) was lower in LNSCs from RA risk individuals than in those from healthy control subjects. Key LN chemokines C-C motif chemokine ligand (CCL19), CCL21 and CXCL13 were induced in LNSCs upon stimulation with tumour necrosis factor-? and lymphotoxin ?1?2, but to a lesser extent in LNSCs from patients with RA. The effect of human LNSCs on T-cell proliferation was ratio-dependent and altered in RA LNSCs. CONCLUSIONS:Overall, we developed an experimental model to facilitate research on the role of LNSCs during the earliest phases of RA. Using this innovative model, we show, for the first time to our knowledge, that the LN stromal environment is changed during the earliest phases of RA, probably contributing to deregulated immune responses early in disease pathogenesis.

Project description:BackgroundLymph node (LN) involvement is an important prognostic indicator for patients with Wilms tumor (WT), and there have been previous reports of utilizing LN density (LND = positive LN/LNs examined) as an advanced metric to risk-stratify patients with WT.ObjectiveThe purpose of this study was to describe patient characteristics that affect LN yield and assess the effect of LND on the overall survival (OS) in patients with WT, with the expectation that patients with LNDs above a critical cut-point would demonstrate lower OS.Study designThe Surveillance, Epidemiology, and End Result (SEER) database was queried for all patients diagnosed with unilateral WT from 2004 to 2015. Patient and disease characteristics were collected, and Poisson regression was used to identify characteristics correlated with LN yield. LND was calculated for LN-positive patients, and multivariable survival analysis was performed, including patient demographics and LND as variables.Results1489 patients with unilateral WT were identified for analysis, 231 (15.51%) of whom were LN-positive. Median patient age at diagnosis was three years (IQR 1-5). On Poisson regression, the year of diagnosis, patient age, tumor size and laterality, and stage were found to impact LN yield. For patients with positive LNs, five-year OS of patients with LNDs above 0.4 was worse than those below 0.4 (76.1% vs 89.6%, p = 0.041). On multivariable analysis, tumor size and LND remained significant predictors of OS.DiscussionAdministrative databases such as SEER provide an excellent resource for studying conditions where large patient numbers for analysis are difficult to obtain. Unfortunately, the SEER database is unable to account for every factor that could affect LN sampling patterns. Additionally, favorable vs unfavorable histology is not available in SEER, and SEER utilizes its own staging system, which makes comparison to Children's Oncology Group staging difficult. Despite these limitations, the findings of this study are similar to those previously published using administrative databases analyzing LN sampling patterns and the effect of LND on OS in WT.ConclusionsAnalysis of the SEER database confirms that there are several patient- and disease-specific factors that affect the number of LNs sampled during nephrectomy for WT, and that LND may be a predictor of OS. These findings highlight the need for standardization of LN sampling patterns for pediatric renal tumors and support the investigation of LND in future studies to further risk-stratify WT patients to tailor therapy intensity.

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Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing.

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Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing.

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