CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?

Ajuebor, Maureen N.; Carey, J. Anne; Swain, Mark G.

doi:10.4049/jimmunol.177.4.2039

Cited by 52 publications

(59 citation statements)

References 63 publications

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“…The CCR5 affects the immune cell function,1 and thus, the CCR5-Δ32 mutation leads to decreased CCR5 expression and influences the function of these cells 3. In agreement with our results, Kalev and colleagues reported a lack of association between CCR5-Δ32 mutation and DN in native Estonian type 2 diabetic patients 2.…”

supporting

confidence: 91%

“…Previous studies demonstrated that a mutation in the unique exon (exon 1) of the CCR5 and deletion of 32 nucleotides (also known as Δ32) leads to decreased expression and function of CCR5 2. Due to its immunomodulatory functions, the CCR5-Δ32 mutation seems to play a key role in autoimmune and inflammatory diseases 3. This study aimed to analyze the CCR5-Δ32 mutation in type 2 diabetic patients with and without diabetic nephropathy (DN).…”

mentioning

confidence: 99%

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Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes?

Arababadi

Naghavi

Hassanshahi

et al. 2009

Annals of Saudi Medicine

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supporting

confidence: 91%

mentioning

confidence: 99%

Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes?

Arababadi

Naghavi

Hassanshahi

et al. 2009

Annals of Saudi Medicine

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“…Moreover, in an in vivo migration experiment, we clearly demonstrated that CXCR3-deficient Tregs were less frequent in the liver of congenic mice upon Con A challenge compared with wt Tregs, verifying an impaired migration capacity of Tregs lacking CXCR3. It has to be remembered that non-lymphoid tissue-homing Tregs also express further chemokine receptors beside CXCR3 (e.g., CCR5 and CCR6), which might also account for Treg recruitment to the inflamed site (27)(28)(29)(30). Hence, we did not expect a complete lack of Tregs in the liver of CXCR3 2/2 mice, and, moreover, a total loss of Treg recruitment to target tissue might have resulted in an even more pronounced phenotype of naive CXCR3 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ–mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10–producing CD4+CD25+Foxp3+ regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3−/− mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3−/− mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3−/− mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3−/− mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3+T-bet+ Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti–IFN-γ Ab treatment demonstrated that conversion to CXCR3+T-bet+ Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4+CD25+Foxp3+ Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3+T-bet+IL-10+ Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.

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“…CCR5, having CCL3 (macrophage inflammatory protein 1␣), CCL4 (macrophage inflammatory protein 1␤), and CCL5 (regulated upon activation, normal T cell expressed and secreted chemokine) as ligands, is also implicated in inflammatory diseases such as rheumatoid arthritis (Prahalad, 2006) and in autoimmune diseases such as multiple sclerosis and type 1 diabetes (Proudfoot, 2002;Ajuebor et al, 2006).…”

mentioning

confidence: 99%

An Intracellular Allosteric Site for a Specific Class of Antagonists of the CC Chemokine G Protein-Coupled Receptors CCR4 and CCR5

Andrews¹,

Jones²,

Wreggett³

2007

Mol Pharmacol

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A novel mechanism for antagonism of the human chemokine receptors CCR4 and CCR5 has been discovered with a series of small-molecule compounds that seems to interact with an allosteric, intracellular site on the receptor. The existence of this site is supported by a series of observations: 1) intracellular access of these antagonists is required for their activity; 2) specific, saturable binding of a radiolabeled antagonist requires the presence of CCR4; and 3) through engineering receptor chimeras by reciprocal transfer of C-terminal domains between CCR4 and CCR5, compound binding and the selective structure-activity relationships for antagonism of these receptors seem to be associated with the integrity of that intracellular region. Published antagonists from other chemical series do not seem to bind to the novel site, and their interaction with either CCR4 or CCR5 is not affected by alteration of the Cterminal domain. The precise location of the proposed binding site remains to be determined, but the known close association of the C-terminal domain, including helix 8, as a proposed intracellular region that interacts with transduction proteins (e.g., G proteins and ␤-arrestin) suggests that this could be a generic allosteric site for chemokine receptors and perhaps more broadly for class A G protein-coupled receptors. The existence of such a site that can be targeted for drug discovery has implications for screening assays for receptor antagonists, which would need, therefore, to consider compound properties for access to this intracellular site.The superfamily of G protein-coupled receptors (GPCRs) represents a productive area for drug discovery. Worldwide sales of drugs that act via GPCRs were estimated in 2004 to be in excess of $120 billion/year (Business Insights Research, 2005). In that same year, chemical programs to target GPCRs accounted for 40% of the portfolio of the pharmaceutical industry, with nearly 40% of these in clinical development (Business Insights Research, 2005).Much of the progress in discovery of small-molecule ligands (i.e., Ͻ500 mol. wt.) for GPCRs comes from improvements in technologies to screen large numbers of compounds, where many campaigns will use functional assays with cell lines genetically engineered to express high amounts of the GPCR of interest, often coexpressed with a genetically modified G protein to improve signaling. This cell-based screening approach is supported by an understanding that the natural agonists for GPCRs interact with extracellular domains of the receptor that form a binding pocket, in analogy with the retinal-binding site of rhodopsin, and from mutagenesis studies of cloned GPCRs, which suggest that antagonists bind competitively at either the orthosteric or a syntopic site within the exofacial core of the transmembrane domains (Kristiansen, 2004). Structural modeling of GPCRs, based on homology with the resolved crystal structures of rhodopsin (Palczewski et al., 2000;Schertler, 2005), also is used to lead rational drug design, and it is ce...

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CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?

Cited by 52 publications

References 63 publications

Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes?

Is CCR5-Δ32 mutation associated with diabetic nephropathy in type 2 diabetes?

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

An Intracellular Allosteric Site for a Specific Class of Antagonists of the CC Chemokine G Protein-Coupled Receptors CCR4 and CCR5

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