Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Liao, Xiaofeng; Ren, Jingjing; Reihl, Alec; Pirapakaran, Tharshikha; Sreekumar, Bharath; Cecere, Thomas E.; Reilly, Christopher M.; Luo, Xin

doi:10.1111/cei.13017

Cited by 26 publications

(25 citation statements)

References 46 publications

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“…This suggests that the combination of pristane and tRA pretreatment may target cDCs in the bone marrow to facilitate glomerulonephritis. This notion is supported by our previous report that activated cDCs from the bone marrow can migrate to the kidney to promote glomerulonephritis in MRL/lpr mice (42). Interestingly, both tRA pre-and post-treatments upon pristane injection significantly expanded the monocytic myeloidderived suppressor cells (MDSCs) gated as Ly6C low/intermediate CD11b + CD11c − compared to pristane alone ( Figure S2A).…”

Section: Enhancement Of Systemic Inflammation By Tra Pre-treatment Insupporting

confidence: 76%

“…Activation of cDCs is required for the induction of glomerular injury and the progression of renal immunopathology in murine models (61,62). Infiltration of activated cDCs into the kidney aggravates the progression of chronic inflammation associated with chronic kidney damage associated with lupus (42,63). Therefore, the results in this study suggest that tRA pre-treatment may have facilitated antigen presentation of apoptotic productswhich are abundant following pristane injection (83)-by MHC-II high cDCs, which subsequently amplified systemic and renal inflammation leading to exacerbated glomerulonephritis.…”

Section: Discussionmentioning

confidence: 99%

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Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

et al. 2020

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We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre-and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

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Section: Enhancement Of Systemic Inflammation By Tra Pre-treatment Insupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

et al. 2020

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“…The serum levels of IL-35 were significantly lower in LN patients than SLE patients without nephritis. Previous investigators have reported that chemokines took part in inflammation via attracting T cells in the target organ (Cao et al 2003;Liao et al 2017). Moreover, increased levels of chemokines in SLE were well confirmed (Wong et al 2008;Munroe et al 2017), and might lead to the accumulation of IL-35 in renal tissue.…”

Section: Discussionmentioning

confidence: 72%

Interleukin-35 as a New Biomarker of Renal Involvement in Lupus Nephritis Patients

Liu

2018

Tohoku J. Exp. Med.

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Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease with a wide range of clinical presentations. Lupus nephritis (LN) is the most serious manifestation of SLE. , a member of the interleukin-12 family, has been identified as a novel anti-inflammatory cytokine. In the past ten years, the role of IL-35 in inflammatory and autoimmune diseases has been studied extensively. Serum IL-35 levels, however, have not been studied in LN patients. The aim of the study was to determine serum IL-35 levels in SLE patients with and without nephritis, and their clinical values. The study was carried out on 120 SLE patients, which comprised 80 LN patients and 40 SLE patients without nephritis. SLE disease activity was measured according to Systemic Lupus Erythematosus Dis ease Activity Index-2 k (SLEDAI-2 k). Statistical evaluation was based on Mann-Whitney U-test, t-test, chi-square test, Spearman rank correlation test and Pearson's correlation test. The result showed that active SLE patients (n = 65) have lower serum IL-35 levels, compared to inactive SLE patients (n = 55, P < 0.001). Furthermore, serum IL-35 levels were significantly lower in LN patients (n = 80) than SLE patients without nephritis (n = 40, P = 0.013). Serum IL-35 levels had significant correlations with SLEDAI-2k (r = -0.626, P < 0.001) in SLE patients and estimated glomerular filtration rate (eGFR) (r = 0.348, P = 0.002) in LN patients. These results indicate that IL-35 is a potential biomarker of renal involvement in LN patients.

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“…Moreover, we have previously demonstrated that FKN expression was increased in LN model mice and HK-2 cells that were stimulated with lipopolysaccharide, whereas the protein expression of FKN was decreased after methylprednisolone therapy (32). Liao et al reported that anti-CX3CR1 (the receptor of FKN) also can attenuate lupus nephritis in murine model (33).…”

Section: Introductionmentioning

confidence: 99%

FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis

Senouthai

Wang

et al. 2019

Front. Immunol.

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Fractalkine (FKN), also known as chemokine (C-X3-C motif) ligand 1, constitutes an intriguing chemokine with a documented role in the development of numerous inflammatory diseases including autoimmune disease. Specifically, it has been reported that FKN is involved in the disease progression of lupus nephritis (LN). The epithelial-mesenchymal transition (EMT) plays a significant role in the formation of tubulointerstitial lesions (TIL), which are increasingly recognized as a hallmark of tissue fibrogenesis after injury. However, the correlation between FKN and EMT or TIL in LN has not been determined. To investigate the potential role of FKN in EMT and TIL, MRL lymphoproliferation (MRL/lpr) strain mice were treated with an anti-FKN antibody, recombinant-FKN chemokine domain, or isotype antibody. Our results revealed that treatment with the anti-FKN antibody improved EMT, TIL, and renal function in MRL/lpr mice, along with inhibiting activation of the Wnt/β-catenin signaling pathway. In contrast, administration of the recombinant-FKN chemokine domain had the opposite effect. Furthermore, to further explore the roles of FKN in EMT, we assessed the levels of EMT markers in FKN-depleted or overexpressing human proximal tubule epithelial HK-2 cells. Our results provide the first evidence that the E-cadherin level was upregulated, whereas α-SMA and vimentin expression was downregulated in FKN-depleted HK-2 cells. In contrast, overexpression of FKN in HK-2 cells enhanced EMT. In addition, inhibition of the Wnt/β-catenin pathway by XAV939 negated the effect of FKN overexpression, whereas activation of the Wnt/β-catenin pathway by Ang II impaired the effect of the FKN knockout on EMT in HK-2 cells. Together, our data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/lpr mice, most likely through activation of the Wnt/β-catenin signaling pathway.

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Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Cited by 26 publications

References 46 publications

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

Interleukin-35 as a New Biomarker of Renal Involvement in Lupus Nephritis Patients

FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis

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