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• W2470063032 abstract "Since the original discovery that immune-mediated inflammation contributes to development and/or progression of obesity and diabetes (reviewed in Gregor and Hotamisligil, 2011Gregor M.F. Hotamisligil G.S. Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (2503) Google Scholar), the identification of the individual immune cell types involved in these diseases remains of broad interest. Mast cells are found at low levels in lean adipose tissue, but their numbers strongly increase in obese adipose tissue. Mast cells are potential sources of proinflammatory factors (including TNF-α), immune-polarizing cytokines (including IL-4), the acute phase protein IL-6, and many tissue-modulating factors, including mast cell proteases, heparin, and histamine, making these cells potential proinflammatory mediators in adipose tissue and in metabolic diseases. Yet whether mast cells play a role in obesity and metabolic syndrome is controversial. In a recent article, Zhou and colleagues reported that mast cells play detrimental roles in obesity and diabetes (Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), a conclusion that directly contradicts our recent report demonstrating that diet-induced or genetic (ob/ob) obesity is not influenced by the presence or absence of mast cells (Gutierrez et al., 2015Gutierrez D.A. Muralidhar S. Feyerabend T.B. Herzig S. Rodewald H.R. Cell Metab. 2015; 21: 678-691Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). This discrepancy can be addressed by analyzing the different mouse models of mast cell deficiency utilized in the two studies. The Shi laboratory, as in the original study (Liu et al., 2009Liu J. Divoux A. Sun J. Zhang J. Clément K. Glickman J.N. Sukhova G.K. Wolters P.J. Du J. Gorgun C.Z. et al.Nat. Med. 2009; 15: 940-945Crossref PubMed Scopus (574) Google Scholar), used a mouse model of mast cell deficiency with a complex genomic rearrangement affecting the Kit locus (KitW-sh/W-sh mice). Although this mouse strain had been proposed by Galli and colleagues as a useful model for analyzing mast cell function in vivo a decade ago (Grimbaldeston et al., 2005Grimbaldeston M.A. Chen C.C. Piliponsky A.M. Tsai M. Tam S.Y. Galli S.J. Am. J. Pathol. 2005; 167: 835-848Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar), subsequent comprehensive analyses of KitW-sh/W-sh mice have revealed severe pleiotropic abnormalities extending beyond mast cell deficiency (Nigrovic et al., 2008Nigrovic P.A. Gray D.H. Jones T. Hallgren J. Kuo F.C. Chaletzky B. Gurish M. Mathis D. Benoist C. Lee D.M. Am. J. Pathol. 2008; 173: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). This mouse strain bears an inversion of approximately 3 Mb of genomic DNA upstream of the Kit coding region (Nigrovic et al., 2008Nigrovic P.A. Gray D.H. Jones T. Hallgren J. Kuo F.C. Chaletzky B. Gurish M. Mathis D. Benoist C. Lee D.M. Am. J. Pathol. 2008; 173: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), which not only affects Kit expression (hence the mast cell deficiency) but also disrupts the Corin gene, causing cardiac hypertrophy, akin to Corin-deficient mice. Moreover, the expression of 27 other genes that are located in the inversion may be affected (Nigrovic et al., 2008Nigrovic P.A. Gray D.H. Jones T. Hallgren J. Kuo F.C. Chaletzky B. Gurish M. Mathis D. Benoist C. Lee D.M. Am. J. Pathol. 2008; 173: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), including genes associated with obesity (Pdgf), blood pressure (Chic2), and signaling in T cells/NK cells (Txk) and macrophages (Tec), as well as an E3 ubiquitin ligase (Lnx) and Cnga1, a gene that is a target of insulin receptor signaling. In addition, immunological analyses of these mice have uncovered defects in spleen and bone marrow, including splenomegaly; megakaryocytosis; neutrophilia; increased frequencies in red blood cell progenitors, in CD11b+ cells, and in Gr1+ cells; decreased frequencies in F4/80+ cells, T cells, and B cells; and expanded Kit+ cells (presumably mast cell progenitors) (Nigrovic et al., 2008Nigrovic P.A. Gray D.H. Jones T. Hallgren J. Kuo F.C. Chaletzky B. Gurish M. Mathis D. Benoist C. Lee D.M. Am. J. Pathol. 2008; 173: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Additionally, there is a 70% increase in circulating neutrophils, as well as thrombocytosis, and expansion of myeloid-derived suppressor cells (MDSCs), consistent with enhanced experimental tumor progression in these mice (which is a mast cell-independent phenomenon too) (Michel et al., 2013Michel A. Schüler A. Friedrich P. Döner F. Bopp T. Radsak M. Hoffmann M. Relle M. Distler U. Kuharev J. et al.J. Immunol. 2013; 190: 5534-5544Crossref PubMed Scopus (35) Google Scholar). In summary, KitW-sh/W-sh mice display many immunological and metabolic phenotypes beyond mast cell deficiency and, in our view, can no longer be regarded as a useful model for studies of mast cell biology. Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar link the resistance of KitW-sh/W-sh mice to obesity and diabetes to the absence of mast cells by showing reversal of this phenotype by injection of bone marrow-derived cultured mast cells (BMMCs). In this regard, it is widely known that following BMMC transfers mast cell compartments are not reliably reconstituted at physiological levels, or with normal tissue distribution, making it difficult to predict the in vivo consequences of this reconstitution (Nakano et al., 1985Nakano T. Sonoda T. Hayashi C. Yamatodani A. Kanayama Y. Yamamura T. Asai H. Yonezawa T. Kitamura Y. Galli S.J. J. Exp. Med. 1985; 162: 1025-1043Crossref PubMed Scopus (397) Google Scholar). This view is supported by the fact that an increasing number of reports using Kit-independent mouse models could not reproduce earlier findings obtained in Kit mutant mice, including cases in which mast cell functions had been deduced based on the BMMC reconstitution system (reviewed in Rodewald and Feyerabend, 2012Rodewald H.R. Feyerabend T.B. Immunity. 2012; 37: 13-24Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar; for more recent examples, see PMIDs 26449668, 24917576, 24689370, 25176657, 25388265, 24406680, 25843682, 25326799, 24416383, and 24227781). Our analysis of the role of mast cells in obesity and insulin resistance was based on the carboxypeptidase A3 (Cpa3) Cre recombinase knockin (Cpa3Cre/+) mouse, a Kit-independent mast cell deficiency model (Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar); yet Zhou et al. write that our results “may not exclude a role of mast cells in obesity and diabetes” (Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Based on the expression pattern of Cpa3, which is indeed not limited to mature mast cells, Zhou et al. argue that the insertion of Cre in Cpa3Cre/+ mice “possibly depleted other cells in addition to mast cells that express the Cpa3 gene, including basophils, some T cell progenitors and thymic T cells, and some hematopoietic progenitor cells” (Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). There are, however, no data to support this claim. With the exception of a reduction in basophils, which we reported (Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), none of these cellular deficiencies have been observed (see below). Cre recombinase is widely used for conditional gene targeting, and Cre toxicity remains an exception rather than a rule. At high expression levels, Cre can be genotoxic in cells; still it does not necessarily affect all cells expressing Cre; therefore each new Cre recombinase strain has to be carefully evaluated. We studied the immune system of Cpa3Cre/+ mice comprehensively and showed that Cpa3 expression correlates with the complete mast cell and the partial basophil ablation (Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). We reported normal numbers and proportions of subsets of peripheral T lymphocytes (naive CD4+, activated/effector memory CD4+, memory CD4+, naive CD8+, activated/effector CD8+, and memory CD8+), of B lymphocytes (transitional type 1, type 2, and type 3 B cells; marginal zone B cells; follicular B cells; B1a; B1b), and of myeloid cells (Gr1+ neutrophils; F4/80+ monocytes; and myeloid, lymphoid, and plasmacytoid dendritic cells) (see Figure S5 in Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar also raised the possibility that some hematopoietic progenitor cells, or thymocytes, may be depleted in Cpa3Cre/+ mice. We compared hematopoietic stem cell (HSC) (see Figure S1A, top row, available online) and progenitor populations in the bone marrow (Figure S1A, bottom row). Specifically, numbers of HSC-containing Lineage−Kit+Sca1+ (KLS+), long-term (LT) HSC, short-term (ST) HSC, and multipotent progenitors (MPPs), as well as numbers of progenitor-containing Lineage−Kit+Sca1− (KLSneg) harboring common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), and megakaryocyte-erythrocyte progenitors (MEPs), and numbers of common lymphoid progenitors (CLPs), do not differ between wild-type Cpa3+/+ and mutant Cpa3Cre/+ mice. There is also no difference comparing Cpa3+/+ and Cpa3Cre/+ mice for thymocyte subsets including early thymic progenitors (ETP), CD4−CD8− (double negative, DN) DN2, DN3, DN4, CD4+CD8+ (double positive, DP), CD4+CD8− single positive (CD4), and CD4−CD8+ (CD8) mature thymocytes (Figure S1B). Additionally, numbers of peripheral αβ TCR or γδ TCR T cells, Treg cells, NK cells, or NK-T cells in the spleen are identical comparing Cpa3+/+ and Cpa3Cre/+ mice (Figure S1C). Finally, further analysis shows that numbers of myeloid cells in the spleen of Cpa3Cre/+ mice are normal for macrophages (Mϕ), neutrophils (Neutro), and eosinophils (Eos) (Figure S1D). As reported earlier (Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), basophils are reduced and mast cells are absent (Figure S1D). In summary, there are no data to suggest that Cre is toxic outside of mast cell and basophil lineages in Cpa3Cre/+ mice. Finally, Zhou et al. make several further statements that we disagree with. The first is that “donor bone marrow cells from Cpa3+/+ and Cpa3Cre/+ mice might correct MC deficiency in KitW/Wv mice” (Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). In fact, the mast cell deficiency is inherent to the bone marrow in Cpa3Cre/+ mice, and hence, while bone marrows from both Cpa3+/+ and Cpa3Cre/+ mice reconstitute general hematopoiesis, only bone marrow from Cpa3+/+ mice, but not from Cpa3Cre/+ mice, can reconstitute mast cells in KitW/Wv mice (Feyerabend et al., 2011Feyerabend T.B. Weiser A. Tietz A. Stassen M. Harris N. Kopf M. Radermacher P. Möller P. Benoist C. Mathis D. et al.Immunity. 2011; 35: 832-844Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Second, healthy normal bone marrow does not contain mature mast cells. The Stevens and Rosenthal reference shows this only for systemic mast cell diseases or reactive mastocytosis, and thus it remains unclear what cells were analyzed for leptin content in Figure 1F in Zhou et al., 2015Zhou Y. Yu X. Chen H. Sjöberg S. Roux J. Zhang L. Ivoulsou A.H. Bensaid F. Liu C.L. Liu J. et al.Cell Metab. 2015; 22: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar. Finally, effects of ketotifen, a drug used in the study of Zhou et al. for pharmacological inhibition, cannot firmly be assigned to mast cells, because this compound is not mast cell-specific (Abu-Dalu et al., 1996Abu-Dalu R. Zhang J.M. Hanani M. Eur. J. Pharmacol. 1996; 309: 189-193Crossref PubMed Scopus (9) Google Scholar). In conclusion, we maintain that mast cell-deficient Cpa3Cre/+ mice are fully susceptible to obesity and diabetes in the presence of an otherwise normal immune system, strongly arguing against mast cell contributions to the pathogenesis of obesity and diabetes. The long-held view of mast cells as essential players in immunity has been appealing. However, when tested in newly developed Kit-independent mast cell deficiency models, many phenotypes formerly attributed to mast cells, including a putative role in obesity and diabetes, are not reproducible, and hence lack independent verification (Morrison, 2014Morrison S.J. eLife. 2014; 3https://doi.org/10.7554/eLife.03981Crossref Google Scholar) in different mouse models. These advances on the grounds of new and improved models should be considered when evaluating existing data and designing future studies on the involvement of mast cells in physiological and pathological processes. Download .pdf (.54 MB) Help with pdf files Document S1. Figure S1" @default.
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• W2470063032 title "Of Mouse Models of Mast Cell Deficiency and Metabolic Syndrome" @default.
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