Questions about Chemokine and Chemokine Receptor Antagonism in Renal Inflammation

Anders, Hans‐Joachim; Sayyed, Sufyan; Vielhauer, Volker

doi:10.1159/000254389

Cited by 10 publications

(14 citation statements)

References 39 publications

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“…Although interference with chemokine action holds great promises for the treatment of inflammatory renal diseases in experimental models, the chemotactic actions of chemokines in both initiation and progression of kidney diseases are much more promiscuous and complicated than we thought. 1,2 Thus, much effort is required to further understand the mechanisms of chemokine function to develop innovative antichemokine therapies for human renal disease. …”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…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. …”

mentioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

237

181

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“…19 In recent years, growing evidence regarding their roles in inflammation, chemokines and their receptors have been proposed to be regarded as attractive therapeutic targets for treatment of inflammatory renal diseases such as glomerulonephritis. 19,20 Indeed, in vivo treatment with an IL-8-blocking antibody reduced glomerular neutrophil accumulation and proteinuria in an acute immune complex glomerulonephritis in rabbits. 21 CXCR1, a receptor of IL-8, has been shown to be expressed on podocytes in vitro and in vivo during membranous glomerulonephritis, 22 as well as on neutrophils in membranoproliferative glomerulonephritis, lupus nephritis, and crescentic glomerulonephritis.…”

Section: 18mentioning

confidence: 99%

Role of CXCR1 (CKR-1) in Inflammation of Experimental Mesangioproliferative Glomerulonephritis

et al. 2013

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CXCR1 (CKR-1), a receptor of IL-8, is expressed in various cells including neutrophils and monocytes, both of which play a major role in proliferating glomerular diseases. We investigated time-dependent expression of CXCR1 and the effect of single-dose cyclosporine A (CsA) treatment on this expression in experimental mesangioproliferative glomerulonephritis induced by anti-thymocyte serum (ATS). Wistar rats were divided into three groups. Group 1 (control, n ¼ 24) received non-immune serum. Group 2 (nephritis, n ¼ 24) received ATS. Group 3 (nephritis þ CsA, n ¼ 24) received ATS and CsA concomitantly. Kidneys from six rats in each group were removed at sixth hour, 3 days, 5 days, and 7 days. ATS induced proteinuria compared to controls (p < 0.001) and CsA precluded the development of proteinuria. Glomerular inflammation and mesangial proliferation were significantly higher in ATS group than control and CsA-treated rats (p < 0.001). ATS injection caused marked interstitial inflammation that was precluded by CsA (p < 0.001). CXCR1 was not expressed in control kidneys. However, ATS induced expression of CXCR1 in both glomeruli and tubulointerstitium. CsA treatment precluded CXCR1 expression in both glomeruli and tubulointerstitium only in the first 6 h. CXCR1 may contribute to inflammation in experimental mesangioproliferative glomerulonephritis. CsA may be beneficial by inhibiting CXCR1 expression and corresponding inflammation.

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“…These studies have produced some surprises. For example, P-selectin deficiency [49,55], Mac-1 deficiency [40] or chemokine blockade [56] paradoxically adversely affect glomerular inflammation. These unexpected results are explained by different processes.…”

Section: Mobilization Of Foot Soldiersmentioning

confidence: 99%

Neutrophils: game changers in glomerulonephritis?

Mayadas

Rosetti

Ernandez

et al. 2010

Trends in Molecular Medicine

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Glomerulonephritides represent a diverse array of diseases that have in common immune cellmediated effector mechanisms that cause organ damage. The contribution of neutrophils to the pathogenesis of proliferative glomerulonephritis (GN) is not well recognized. Most equate neutrophils with killing pathogens and causing collateral tissue damage during acute inflammation. However, these phagocytes are endowed with additional characteristics that have been traditionally reserved for cells of the adaptive immune system. They communicate with other cells, exhibit plasticity in their responses and have the potential to coordinate and inform the subsequent immune response, thus countering the notion that they arrive, destroy and then disappear. Therefore, neutrophils, which are the first to arrive at a site of inflammation, are potential game changers in GN.

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Questions about Chemokine and Chemokine Receptor Antagonism in Renal Inflammation

Cited by 10 publications

References 39 publications

Chemokines in Renal Injury

Chemokines in Renal Injury

Role of CXCR1 (CKR-1) in Inflammation of Experimental Mesangioproliferative Glomerulonephritis

Neutrophils: game changers in glomerulonephritis?

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