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Peroxisome proliferator-activated receptor ? B cell-specific-deficient mice have an impaired antibody response.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR?, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPAR? is expressed in most bone marrow-derived cells and influences their function. PPAR? ligands can stimulate human B cell differentiation and promote Ab production. A knowledge gap is that the role of PPAR? in B cells under physiological conditions is not known. We developed a new B cell-specific PPAR? (B-PPAR?) knockout mouse and explored the role of PPAR? during both the primary and secondary immune response. In this article, we show that PPAR? deficiency in B cells decreases germinal center B cells and plasma cell development, as well as the levels of circulating Ag-specific Abs during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPAR?-deficient mice have an impaired memory response, characterized by low titers of Ag-specific Abs and low numbers of Ag-experienced, Ab-secreting cells. However, B-PPAR?-deficient mice have no differences in B cell population distribution within primary or secondary lymphoid organs during development. This is the first report, to our knowledge, to show that, under physiological conditions, PPAR? expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and Ab production.

SUBMITTER: Ramon S

PROVIDER: S-EPMC3490033 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

Ramon Sesquile S Bancos Simona S Thatcher Thomas H TH Murant Thomas I TI Moshkani Safiehkhatoon S Sahler Julie M JM Bottaro Andrea A Sime Patricia J PJ Phipps Richard P RP

Journal of immunology (Baltimore, Md. : 1950) 20121005 10

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARγ is expressed in most bone marrow-derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote Ab production. A kn ...[more]

PMID: 23041568

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Project description:Although glucocorticoids (GC) represent the most frequently used immunosuppressive drugs, their effects are still not well understood. In our previous studies, we have shown that treatment of monocytes with GC does not cause a global suppression of monocytic effector functions, but rather induces differentiation of a specific anti-inflammatory phenotype. The anti-inflammatory role of peroxisome proliferator-activated receptor (PPAR)-? has been extensively studied during recent years. However, a relationship between GC treatment and PPAR-? expression in macrophages has not been investigated so far. Studies using PPAR-?-deficient mice have frequently provided controversial results. A potential reason is the use of primary cells, which commonly represent inhomogeneous populations burdened with side effects and influenced by bystander cells. To overcome this constraint, we established ER-Hoxb8-immortalized bone marrow-derived macrophages from Ppargfl/fl and LysM-Cre Ppargfl/fl mice in this study. In contrast to primary macrophages, the ER-Hoxb8 system allows the generation of a homogeneous and well-defined population of resting macrophages. We could show that the loss of PPAR-? resulted in delayed kinetic of differentiation of monocytes into macrophages as assessed by reduced F4/80, but increased Ly6C expression in early phases of differentiation. As expected, PPAR-?-deficient macrophages displayed an increased pro-inflammatory phenotype upon long-term LPS stimulation characterized by an elevated production of pro-inflammatory cytokines TNF-?, IL1-?, IL-6, IL-12 and a reduced production of anti-inflammatory cytokine IL-10 compared to PPAR-? WT cells. Moreover, PPAR-?-deficient macrophages showed impaired phagocytosis. GC treatment of macrophages led to the upregulation of PPAR-? expression. However, there were no differences in GC-induced suppression of cytokines between both cell types, implicating a PPAR-?-independent mechanism. Intriguingly, GC treatment resulted in an increased in vitro migration only in PPAR-?-deficient macrophages. Performing a newly developed in vivo cell-tracking experiment, we could confirm that GC induces an increased recruitment of PPAR-? KO, but not PPAR-? WT macrophages to the site of inflammation. Our findings suggest a specific effect of PPAR-? on GC-induced migration in macrophages. In conclusion, we could demonstrate that PPAR-? exerts anti-inflammatory activities and shapes macrophage functions. Moreover, we identified a molecular link between GC and PPAR-? and could show for the first time that PPAR-? modulates GC-induced migration in macrophages.

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Peroxisome proliferator-activated receptor ? B cell-specific-deficient mice have an impaired antibody response.

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Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

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