Estrogen Regulates CCR Gene Expression and Function in T Lymphocytes

Mo, Ru Ran; Chen, Jun; Grolleau-Julius, Annabelle; Murphy, Hedwig S.; Richardson, Bruce C.; Yung, Raymond

doi:10.4049/jimmunol.174.10.6023

Cited by 107 publications

(84 citation statements)

References 61 publications

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“…High serum concentrations of TNF-a, TGF-b, and IFN-g have been reported in lupus nephritis, and these cytokines are known to induce Ccr1 gene expression, notably in myeloid and T cells (38,39). Estrogens that regulate inflammation may amplify this phenomenon (40,41). However, epigenetic (e.g., promoter hypomethylation) or posttranscriptional (e.g., microRNA) regulatory mechanisms could account for the increased steady-state levels of Ccr1 mRNAs in nephritic NZB/W mice.…”

Section: Discussionmentioning

confidence: 99%

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Bignon

Gaudin

Hémon

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4+ T cells, Ly6C+ monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.

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Section: Discussionmentioning

confidence: 99%

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Bignon

Gaudin

Hémon

et al. 2014

The Journal of Immunology

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“…Altogether, these observations suggest that endogenous estrogens might modulate leukocyte trafficking to the CNS rather than MOG-specific T-cell development. There is some evidence that endogenous estrogens can regulate chemokine receptor expression and function in T lymphocytes [26]. Recently, CCR6 expression by Th17 cells has been shown to be important for the initiation of CNS inflammation in EAE [27].…”

Section: Discussionmentioning

confidence: 99%

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

et al. 2010

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Sex hormones influence immune responses and the development of autoimmune diseases including MS and its animal model, EAE. Although it has been previously reported that ovariectomy could worsen EAE, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been addressed. In this report, we now show that endogenous estrogens limit EAE development and CNS inflammation in adult female mice through estrogen receptor a expression in the host non-hematopoietic tissues. We provide evidence that the enhancing effect of gonadectomy on EAE development was due to quantitative rather than qualitative changes in effector Th1 or Th17 cell recruitment into the CNS. Consistent with this observation, adoptive transfer of myelin oligodendrocyte glycoprotein-specific encephalitogenic CD41 T lymphocytes induced more severe EAE in ovariectomized mice as compared to normal female mice. Finally, we show that gonadectomy accelerated the early recruitment of inflammatory cells into the CNS upon adoptive transfer of encephalitogenic CD4 1 T cells. Altogether, these data show that endogenous estrogens, through estrogen receptor a, exert a protective effect on EAE by limiting the recruitment of blood-derived inflammatory cells into the CNS.Key words: EAE/MS . Estrogen . Estrogen receptor . Inflammation . Th1/Th17 cells Supporting Information available onlineIntroduction MS and its prototypic animal model, EAE, are autoimmune demyelinating diseases of the CNS. In MS and EAE, the inflammatory process is mediated by T lymphocytes reactive to CNS and brain autoantigens. It is well documented that sex hormones could influence immune responses and the development of autoimmune diseases including MS and EAE [1]. Indeed, protective effects of exogenous estrogens have been extensively reported in animal models of EAE [2][3][4]. The actions of estrogens are mediated primarily through nuclear estrogen receptor (ER) a and ERb [5]. Analysis of the effect of exogenous 17b-estradiol 3489(E2) on EAE induction in ER-mutant mice clearly showed that this protective effect of E2 was mediated through ERa but not ERb [6][7][8]. Altogether, these studies support a protective role of estrogens on EAE that could explain the protective effect of pregnancy on MS [9]. Indeed, a clinical trial in women with MS has documented a beneficial effect of exogenous estriol administration [10]. Thus, although it has been shown that exogenous estrogens down modulate EAE through ERa, it is still unclear whether physiological levels of endogenous estrogens can significantly influence CNS autoimmunity [11,12]. In female mice, sex steroid hormones, such as estrogens, are mainly produced by the ovaries, and previous studies have reported that ovariectomy could worsen EAE [2,13,14]. However, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been previously examined. For instance, it is still unknown whether these effects were due to ovarian-derived estrogens or other gonadal hormones, and whether classical ER...

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“…Cyclical changes in estradiol concentrations in women have been associated with changes in lung adrenergic receptor density and in concentrations of mucus, acetylcholine, and prostaglandin (4). Estradiol also increases T cell expression of receptors for CC chemokines and alters T cell homing patterns (65). Interestingly, analysis of bronchoalveolar fluid in healthy individuals showed a significantly increased percentage of CD4ϩ T cells in women over age 43, compared with men and with younger women (66).…”

Section: Potential Sex-specific Differences In Smaller Airways and Pamentioning

confidence: 99%

Sex Differences in Severe Pulmonary Emphysema

Martínez

Curtis

Sciurba

et al. 2007

Am J Respir Crit Care Med

303

219

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Rationale: Limited data on sex differences in advanced COPD are available. Objectives: To compare male and female emphysema patients with severe disease. Methods: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed. Measurements and Main Results: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n ϭ 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower DL CO and arterial PO 2 , higher arterial PCO 2 , shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV 1 % predicted, age, number of packyears, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters. Conclusions: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement. What This Study Adds to the FieldIn patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.

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Estrogen Regulates CCR Gene Expression and Function in T Lymphocytes

Cited by 107 publications

References 61 publications

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

Sex Differences in Severe Pulmonary Emphysema

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Estrogen Regulates CCR Gene Expression and Function in T Lymphocytes

Cited by 107 publications

References 61 publications

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4+ T‐cell homing into the CNS

Sex Differences in Severe Pulmonary Emphysema

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Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS