Elevated Levels of Fractalkine Expression and Accumulation of CD16+ Monocytes in Glomeruli of Active Lupus Nephritis

Yoshimoto, Shuhei; Nakatani, Katsunori; Iwano, Masayuki; Asai, Osamu; Samejima, Ken ichi; Sakan, Hirokazu; Terada, Miho; Harada, Koji; Akai, Yasuhiro; Sasaki, Hideo; Nose, Masato; Saito, Yoshihiko

doi:10.1053/j.ajkd.2007.04.012

Cited by 99 publications

(107 citation statements)

References 35 publications

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“…In the glomerular compartment, few T cells, even fewer B cells and no dendritic cells are typically present. 29,46,47 Thus, macrophages, which we and others 48 could identify in glomeruli with lupus nephritis, may have a prominent role. Chang et al 9 show in vitro that BLyS stimulation of TACI expressing monocytes led to the enhancement of their survival and their activation.…”

Section: Discussionmentioning

confidence: 50%

Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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The B-cell survival factors APRIL and BLyS are important for B-cell maturation and activation and contribute to human autoimmune diseases. Interference with B-cell function by targeting these molecules is currently being investigated in large clinical trials for systemic lupus erythematosus. The local expression patterns of APRIL and BLyS have not been investigated in detail in kidneys with lupus nephritis. We studied the mRNA expression of APRIL, BLyS, and the corresponding receptors BCMA, TACI, and BAFF-R in microdissected human biopsies with proliferative lupus nephritis (n ¼ 25) and compared it with pretransplant biopsies of living donors (n ¼ 9). APRIL and BLyS mRNA levels were significantly higher in glomeruli of patients with proliferative lupus nephritis (12-and 30-fold, respectively). Tubulointerstitial expression of APRIL, BLyS, BCMA, and TACI was also significantly elevated. To localize the respective proteins in the kidney, APRIL, BLyS, and BAFF-R were studied by immunohistochemistry in renal biopsies with proliferative (n ¼ 21) or membranous (n ¼ 8) lupus nephritis. APRIL was prominently expressed in glomeruli with proliferative, but not membranous, lupus nephritis. The staining pattern was consistent with mesangial cells. A prominent accumulation of CD68-positive cells was present in glomeruli in association with APRIL expression. APRIL, BLyS, and BAFF-R were also expressed in interstitial inflammatory cell accumulation. This is the first study, which details local expression of APRIL and BLyS in glomeruli and tubulointerstitium of human proliferative lupus nephritis. This information might help define intrarenal effects of APRIL and BLyS inhibition in human lupus nephritis.

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Section: Discussionmentioning

confidence: 50%

Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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“…7, 2018; be activated through TLR7 and TLR8 to produce inflammatory cytokines via sensing of nucleic acids produced by damaged cells 60 . Glomerular CD68 + macrophages have been reported in many histologic studies of LN, suggesting patrolling behavior, and are associated with more severe clinical disease in a subset of LN patients 60,61 . Our study suggests that the three subpopulations of CD16 + related macrophages identified here may transition through an inflammatory to a resolution phase.…”

Section: Cc-by-nc-nd 40 International License It Is Made Available Umentioning

confidence: 95%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

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Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

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“…75,76 Like AKI, fractalkine/CX3CL1 is also detected in renal biopsies from patients with progressive kidney injury. [77][78][79] Fractalkine/CX3CL1 and its receptor CX3CR are upregulated during renal injury in several mouse models, including experimental folic acid nephropathy, crescentic GN, and diabetic nephropathy. 80,81,78,82,83,77,9 Treatment with a neutralizing antibody against fractalkine/CX3CL1 improves renal damage by blocking crescentic formation and macrophage infiltration in rat nephrotoxic nephritis.…”

Section: Role Of CCL and Cx3cl Chemokines In Chronic Kidney Diseasementioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

237

181

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Renal inflammation underlies many chronic kidney diseases and the infiltration of leukocytes mediates much of the nephritogenic inflammatory response. As several recent reviews have dealt with the basic biology, mouse models, and blockade studies of chemokines in renal diseases, [1][2][3][4][5][6][7][8][9][10][11] we focus here on recent developments in pathophysiology of that chemokine effect. CHEMOKINES AND CHEMOKINE RECEPTORSChemokines are a group of chemotactic cytokines (approximately 8 to 17 kD) with the ability to bind G-proteincoupled receptors and act as potent attractants for leukocytes in acute and chronic inflammation. There are four subfamilies of chemokines, including CCL, CXCL, CX3CL, and CL (Figure 1). 7,6 At present, 19 receptors are known ( Figure 1). 6,7 The large CC chemokine family has the first two cysteine residues adjacent to each other, whereas the CXC family has a single amino acid residue in between the first two cysteines. Fractalkine (CX3CL1) is the only member of the CX3C chemokine family where three amino acid residues separate the first two cysteines. Finally, two related chemokines absent the two cysteine residues that bind the XCR1 receptor belong to the XC family. As shown in Figure 1, many chemokines bind multiple receptors and most receptors bind multiple chemokines. However, CC chemokine receptors exclusively bind CC chemokines and CXC receptors bind only CXC chemokines.Chemokines and their corresponding receptors are expressed in different cell types (Figure 2). 7,12 Generally speaking, monocytes are mostly attracted by CCL chemokines acting through CCR1, CCR2, andCCR5receptors,whereasneutrophilsare the target of CXCL chemokines through REGULATION OF CHEMOKINE EXPRESSIONOn the basis of their regulation and production, chemokines can be classified broadly as homeostatic/lymphoid or inflammatory chemokines. The former is responsible for leukocyte homing and ABSTRACTThe main function of chemokines is to guide inflammatory cells in their migration to sites of inflammation. During the last 2 decades, an expanding number of chemokines and their receptors have driven broad inquiry into how inflammatory cells are recruited in a variety of diseases. Although this review focuses on chemokines and their receptors in renal injury, proinflammatory IL-17, TGF␤, and TWEAK signaling pathways also play a critical role in their expression. Recent studies in transgenic mice as well as blockade of chemokine signaling by neutralizing ligands or receptor antagonists now allow direct interrogation of chemokine action. The emerging role of regulatory T cells and Th17 cells during renal injury also forges tight relationships between chemokines and T cell infiltration in the development of kidney disease. As chemokine receptor blockade inches toward clinical use, the field remains an attractive area with potential for unexpected opportunity in the future.

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Elevated Levels of Fractalkine Expression and Accumulation of CD16+ Monocytes in Glomeruli of Active Lupus Nephritis

Cited by 99 publications

References 35 publications

Intrarenal production of B-cell survival factors in human lupus nephritis

Intrarenal production of B-cell survival factors in human lupus nephritis

The immune cell landscape in kidneys of lupus nephritis patients

Chemokines in Renal Injury

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