T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis

Phoon, Richard K.S.; Kitching, A. Richard; Odobasic, Dragana; Jones, Lynelle K.; Semple, Timothy; Holdsworth, Stephen R.

doi:10.1681/asn.2007030392

Cited by 59 publications

(76 citation statements)

References 45 publications

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“…35 On the other hand, abrogation of Th1 signaling by deleting the T-bet gene, a transcription factor for Th1 cells, not only attenuates glomerular crescent formation and accumulation of CD4 ϩ T cells and macrophages, but it also reduces intrarenal expression of RANTES/ CCL5, Mig/CXCL9, and CXCR3. 89 However, injection of Th1 cells in mice increases renal expression of MCP1/ CCL2 and RANTES/CCL5, and causes progressive albuminuria along with crescent formation. 24 Taken together, CCL chemokines participate in activating infiltrating cells related to Th1 immune responses during inflammatory renal injury.…”

Section: Role Of Chemokines In T Cell Infiltration During Kidney Injurymentioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

240

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: Role Of Chemokines In T Cell Infiltration During Kidney Injurymentioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

240

181

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“…Realtime PCR was performed on a Rotor Gene RG-3000 (Corbett Research, Mortlake, VIC, Australia) for measurement of T-bet, GATA3, RORgt, IFN-g, IL-4, TNF, IL-6, MAPK phosphatase-1 (MKP-1), glucocorticoidinduced leucine zipper (GILZ), and b-actin using Power SYBR Green PCR Master Mix (Applied Biosystems). Gene-specific oligonucleotide primers were used and synthesized by Invitrogen, as previously described (13,(29)(30)(31). TaqMan-predesigned real-time PCR assays (Applied Biosystems) were used for detection of IL-17A and IL-10.…”

Section: Real-time Pcrmentioning

confidence: 99%

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Yang

Song

Deane

et al. 2013

The Journal of Immunology

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Annexin A1 (AnxA1) is recognized as an endogenous anti-inflammatory molecule. However, its effects on the adaptive immune response and, in particular, on T cells remain unclear. In this study, we investigated the actions of AnxA1 in three distinct models of T cell–mediated inflammation. In contact hypersensitivity, collagen-induced arthritis, and inflammation induced by OT-II TCR transgenic T cells responding to OVA, AnxA1 deficiency significantly increased Ag-induced T cell proliferation and the resultant level of inflammation. In the contact hypersensitivity model, this was associated with increased adhesion of CD4+ T cells, CD8+ T cells, and neutrophils in the dermal microvasculature, as well as increased T cell expression of RORγt and IL-17A. In collagen-induced arthritis, deficiency of endogenous AnxA1 increased susceptibility to arthritis and Ag-specific T cell activation. Deficiency of AnxA1 also increased OVA-induced cutaneous delayed-type hypersensitivity and IFN-γ and IL-17 release. Transfer experiments using CD4+ T cells from AnxA1−/− mice demonstrated that the absence of AnxA1 solely in T cells resulted in increased inflammatory responses in wild-type recipients. Similarly, experiments using AnxA1−/− OT-II CD4+ T cells demonstrated that the absence of AnxA1 in T cells was sufficient to induce increased Ag-specific CD4+ T cell proliferation in vivo, augment T cell production of IFN-γ, IL-17, TNF, and IL-6, and increase Akt, ERK, and p38 activation. Together, these findings indicate that T cell–expressed AnxA1 functions to attenuate T cell–driven inflammatory responses via T cell–intrinsic effects on intracellular signaling, proliferation, and Th1/Th17 cytokine release.

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“…9,10 Studies in patients with crescentic GN and experimental models of GN have shown the importance of CD4 + T cell-driven immune responses in this disease group. 9 Today, there is clear evidence that the recruitment of T H 1 11,12 and T H 17 [13][14][15] cells into the inflamed kidney drives renal tissue damage, whereas Tregs suppress overwhelming immune responses. [16][17][18] In this study, we investigated the functional role of chemokine receptors expressed on Tregs in crescentic GN.…”

mentioning

confidence: 99%

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

Paust¹,

Riedel²,

Krebs³

et al. 2015

JASN

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Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the T H 1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3 + effector T cells.

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T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis

Cited by 59 publications

References 45 publications

Chemokines in Renal Injury

Chemokines in Renal Injury

Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

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