New models for analyzing mast cell functions in vivo

ArticleinTrends in Immunology 33(12) · November 2012with22 Reads
DOI: 10.1016/j.it.2012.09.008 · Source: PubMed
Abstract
In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency.
    • "Human plasma concentrations of tryptase, a MC-specific enzyme, increase with rising body mass index (BMI) (Fenger et al., 2012) and correlate with body fat mass, glycated hemoglobin, fasting insulin level, and homeostasis model assessment-estimated insulin resistance (HOMA-IR) index (Ramalho et al., 2012). Although a recent study using anemic MC-deficient Kit W/Wv mice and Cpa Cre/+ mice that affect more than just MCs (Reber et al., 2012) claimed a negligible role of MCs in obesity and diabetes (Gutierrez et al., 2015), MC stabilizer ketotifen reduces BMI, HbA1c, fasting blood glucose, low-density lipoproteins, and triglyceride, and increases adiponectin and high-density lipoproteins among obese and diabetic patients (El-Haggar et al., 2015). Macrophages (F4/80 + CD11b + ) drive obesity-associated inflammation and diseases. "
    [Show abstract] [Hide abstract] ABSTRACT: Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
    Full-text · Article · Oct 2015
    • "As for mast cells, Kit-mediated immunological and non-immunological roles can now be discriminated from those of mast cells by employing mast-cell-specific deficiency mouse models (for detailed considerations, see Katz and Austen, 2011; Peschke et al., 2015; Reber et al., 2012; Rodewald and Feyerabend, 2012). There are several Kit-independent models of mast cell deficiency, both constitutive and inducible (reviewed in Reber et al., 2012), and careful attention must be placed on choosing the appropriate model for the study of choice. In our view, Cpa3 Cre/+ mice presented the most suitable model for the current study, as it is the only mouse with complete deficiency of both connective and mucosal tissue mast cells without deficiencies in other immune or non-immune compartments , with the exception of a reduction in basophils. "
    [Show abstract] [Hide abstract] ABSTRACT: Graphical Abstract Highlights d Obesity and insulin resistance are unaffected by mast cell deficiency d Global Kit deficiency protects mice from obesity and associated metabolic disorders d Reconstitution of Kit mutant mice with Kit +/+ HSCs normalizes metabolic phenotype In Brief Mice with Kit mutations have several immune and non-immune abnormalities, including mast cell deficiency, and are protected from weight gain and insulin resistance during diet-induced obesity. Gutierrez et al. show that this protection is not mediated by mast cell deficiency, as previously thought, but instead through hematopoietic Kit deficiency.
    Full-text · Article · Apr 2015
    • "This is particularly due to the debatable evidence of a causal relationship between mast cell infiltrates and tumor progression in humans. In addition, the use of mast cell-deficient models has been recently challenged by the characterization of new specific models of mast cell ablation [21,29]. Therefore, the role of mast cell infiltrates in tumors is still unclear and merits particular attention. "
    [Show abstract] [Hide abstract] ABSTRACT: Mast cells are immune cells that accumulate in the tumors and their microenvironment during disease progression. Mast cells are armed with a wide array of receptors that sense environment modifications and, upon stimulation, they are able to secrete several biologically active factors involved in the modulation of tumor growth. For example, mast cells are able to secrete pro-angiogenic and growth factors but also pro- and anti-inflammatory mediators. Recent studies have allowed substantial progress in understanding the role of mast cells in tumorigenesis/disease progression but further studies are necessary to completely elucidate their impact in the pathophysiology of cancer. Here we review observations suggesting that mast cells could modulate tumor growth in humans. We also discuss the drawbacks related to observations from mast cell-deficient mouse models, which could have consequences in the determination of a potential causative relationship between mast cells and cancer. We believe that the understanding of the precise role of mast cells in tumor development and progression will be of critical importance for the development of new targeted therapies in human cancers.
    Full-text · Article · Jan 2015
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