CCR6 Recruits Regulatory T Cells and Th17 Cells to the Kidney in Glomerulonephritis

Turner, Jan-Eric; Paust, Hans‐Joachim; Steinmetz, Oliver M.; Peters, Anett; Riedel, Jan-Hendrik; Erhardt, Annette; Wegscheid, Claudia; Velden, Joachim; Fehr, Susanne; Mittrücker, Hans‐Willi; Tiegs, Gisa; Stahl, Rolf A.K.; Panzer, Ulf

doi:10.1681/asn.2009070741

Cited by 163 publications

(187 citation statements)

References 33 publications

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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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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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“…To quantify glomerular and tubular tissue damage, PASstained kidney sections were evaluated as previously described. 9 The frequency of glomerular crescent formation on day 7 of NTN was significantly increased in Foxp3 YFP-Cre x Il10 flox/flox mice, which selectively lack IL-10-producing Tregs, in contrast to IL-10-competent Il10 flox/flox mice ( Figure 5, A and B). This effect was more pronounced 14 days upon induction of NTN ( Figure 5C).…”

Section: Aggravated Ntn In Mice Lacking Il-10-producing Tregsmentioning

confidence: 95%

“…Primer pairs were used as described previously. 9,11 Relative mRNA levels were calculated after normalization to 18S rRNA using CFX96 Manager software.…”

Section: Real-time Qualitative Rt-pcr Analysismentioning

confidence: 99%

“…9,39 In brief, kidneys were finely minced and digested for 40 minutes at 37°C with 0.4 mg/ml collagenase D (Roche, Mannheim, Germany) and 0.01 mg/ml DNAse I in RPMI 1640 medium supplemented with 10% heat-inactivated FCS (Invitrogen). Cell suspensions were filtered through 70-and 40-mm nylon meshes and washed with HBSS without Ca 2+ and Mg 2+ (Life Technologies GmbH, Darmstadt, Germany).…”

Section: Leukocyte Isolation From Various Tissuesmentioning

confidence: 99%

“…Adoptive cell transfer experiments in mice showed the beneficial role of exogenous wild-type (wt) CD4 + CD25 + Tregs in attenuation of crescentic GN, 8 whereas CCR6-and CCR7-deficient CD4 + CD25 + Tregs failed to protect mice against GN. 9,10 Recently, our own published data revealed the importance of endogenous Foxp3 + Tregs in suppressing the Th1 immune response and consequently ameliorating the disease severity in the T cell-dependent GN model of nephrotoxic nephritis (NTN). 11 Concurrently, Ooi and coworkers confirmed the relevance of endogenous Foxp3 + Tregs in an accelerated model of experimental crescentic GN.…”

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Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Ostmann¹,

Paust²,

Panzer³

et al. 2013

Journal of the American Society of Nephrology

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Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10-producing Foxp3 + T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3 + Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNg and IL-17; these IL-10-deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.

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Calcium/Calmodulin‐Dependent Kinase IV Facilitates the Recruitment of Interleukin‐17–Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell–Driven Inflammatory Diseases

Koga

Otomo

Mizui

et al. 2016

Arthritis & Rheumatology

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Objective The recruitment of IL-17-producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of CaMK4 activation on Th17-cell recruitment to target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE. Methods We induced experimental AIGN in Camk4-sufficient or -deficient mice and compared histology, Th17-related chemokine expression and numbers of IL-17-producing cells in the kidneys. We also evaluated the efficacy of the CaMK4 antagonist KN-93 in alter AIGN induced kidney disease. The expression of CCR6 in memory CD4 T cells before AIGN induction was analyzed by flow cytometry. We investigated the correlation between CCR6 expression in the peripheral blood and the severity of glomerulonephritis in patients with SLE. Results Camk4-deficient mice displayed less glomerular injury after the induction of AIGN. Kidney infiltration by IL-17-producing CD4 T cells along with CCR6 and CCL20 expression were significantly decreased in Camk4-deficient mice. Similarly, the KN-93 treatment of mice prior to exposure to AIGN improved the clinical and pathological finings. The expression and function of CCR6 in memory CD4 T cells in the peripheral blood was decreased in the Camk4-deficient mice. The expression of CCR6 correlated positively with the severity of organ damage in SLE patients. Conclusion Our results indicate that CaMK4 represents a novel therapeutic strategy for the treatment of Th17 cell-mediated tissue damage in inflammatory diseases.

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CCR6 Recruits Regulatory T Cells and Th17 Cells to the Kidney in Glomerulonephritis

Cited by 163 publications

References 33 publications

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

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

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Calcium/Calmodulin‐Dependent Kinase IV Facilitates the Recruitment of Interleukin‐17–Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell–Driven Inflammatory Diseases

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