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Article ; Online: Contribution of alternatively activated macrophages to allergic lung inflammation: a tale of mice and men.

Dasgupta, Preeta / Keegan, Achsah D

2012 Volume 4, Issue 5-6, Page(s) 478–488

Abstract: The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705-712 and ...

Abstract	The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705-712 and Cavaillon JM: J Leukoc Biol 2011;90:413-424]. Based on his observation of the phagocyte response to a foreign body (rose thorn) and yeast, he proposed that phagocytes acted in host defense and were active participants in the inflammatory process. Flash forward more than 100 years and we find that these basic tenets hold true. However, it is now appreciated that macrophages come in many different flavors and can adopt a variety of nuanced phenotypes depending on the tissue environment in which the macrophage is found. In this brief review, we discuss the role of one type of macrophage termed the alternatively activated macrophage (AAM), also known as the M2 type of macrophage, in regulating allergic lung inflammation and asthma. Recent studies using mouse models of allergic lung inflammation and samples from human asthma patients contribute to the emerging concept that AAMs are not just bystanders of the interleukin (IL)-4- and IL-13-rich environment found in allergic asthma but are also active players in orchestrating allergic lung disease.
MeSH term(s)	Adult ; Animals ; Asthma/immunology ; Asthma/physiopathology ; Child ; Child, Preschool ; Humans ; Hypersensitivity/immunology ; Hypersensitivity/physiopathology ; Interleukin-13/metabolism ; Interleukin-4/metabolism ; Macrophage Activation/immunology ; Macrophages, Alveolar/immunology ; Mice ; Pneumonia/immunology ; Pneumonia/physiopathology
Chemical Substances	Interleukin-13 ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2012-03-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000336025
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Article: Contribution of Alternatively Activated Macrophages to Allergic Lung Inflammation: A Tale of Mice and Men

Dasgupta, Preeta / Keegan, Achsah D.

Journal of Innate Immunity

2012 Volume 4, Issue 5-6, Page(s) 478–488

Institution	Center for Vascular and Inflammatory Diseases, Marlene and Stewart Greenebaum Cancer Center, and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Md., USA
Abstract	The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705–712 and Cavaillon JM: J Leukoc Biol 2011;90:413–424]. Based on his observation of the phagocyte response to a foreign body (rose thorn) and yeast, he proposed that phagocytes acted in host defense and were active participants in the inflammatory process. Flash forward more than 100 years and we find that these basic tenets hold true. However, it is now appreciated that macrophages come in many different flavors and can adopt a variety of nuanced phenotypes depending on the tissue environment in which the macrophage is found. In this brief review, we discuss the role of one type of macrophage termed the alternatively activated macrophage (AAM), also known as the M2 type of macrophage, in regulating allergic lung inflammation and asthma. Recent studies using mouse models of allergic lung inflammation and samples from human asthma patients contribute to the emerging concept that AAMs are not just bystanders of the interleukin (IL)-4- and IL-13-rich environment found in allergic asthma but are also active players in orchestrating allergic lung disease.
Keywords	Interleukin-4 ; Interleukin-13 ; Macrophages ; Asthma
Language	English
Publishing date	2012-03-21
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Review
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000336025
Database	Karger publisher's database

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Article ; Online: Contribution of Alternatively Activated Macrophages to Allergic Lung Inflammation: A Tale of Mice and Men

Dasgupta, Preeta / Keegan, Achsah D.

Journal of Innate Immunity

2012 Volume 4, Issue 5-6, Page(s) 478–488

Abstract	The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705-712 and Cavaillon JM: J Leukoc Biol 2011;90:413-424]. Based on his observation of the phagocyte response to a foreign body (rose thorn) and yeast, he proposed that phagocytes acted in host defense and were active participants in the inflammatory process. Flash forward more than 100 years and we find that these basic tenets hold true. However, it is now appreciated that macrophages come in many different flavors and can adopt a variety of nuanced phenotypes depending on the tissue environment in which the macrophage is found. In this brief review, we discuss the role of one type of macrophage termed the alternatively activated macrophage (AAM), also known as the M2 type of macrophage, in regulating allergic lung inflammation and asthma. Recent studies using mouse models of allergic lung inflammation and samples from human asthma patients contribute to the emerging concept that AAMs are not just bystanders of the interleukin (IL)-4- and IL-13-rich environment found in allergic asthma but are also active players in orchestrating allergic lung disease.
Keywords	Interleukin-4 ; Interleukin-13 ; Macrophages ; Asthma
Language	English
Publisher	S. Karger AG
Publishing place	Basel
Publishing country	Switzerland
Document type	Article ; Online
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000336025
Database	Karger publisher's database

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Article ; Online: Absence of the common gamma chain (γ(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation.

Dasgupta, Preeta / Qi, Xiulan / Smith, Elizabeth P / Keegan, Achsah D

PloS one

2013 Volume 8, Issue 8, Page(s) e71344

Abstract: The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma ... ...

Abstract	The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γ(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4⁺ OT-II T cells were adoptively transferred into RAG2⁻/⁻ and γ(c)⁻/⁻ mice and allergic lung disease was induced. Both γ(c)⁻/⁻ and γcxRAG2⁻/⁻ mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2⁻/⁻ mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γ(c)⁻/⁻ mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the γ(c)⁻/⁻ recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γ(c)-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages.
MeSH term(s)	Animals ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Dendritic Cells/physiology ; Gene Deletion ; Hypersensitivity/complications ; Hypersensitivity/genetics ; Hypersensitivity/immunology ; Interleukin Receptor Common gamma Subunit/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pneumonia/complications ; Pneumonia/genetics ; Pneumonia/immunology ; Receptors, Interleukin-4/genetics ; Severity of Illness Index ; Th2 Cells/physiology
Chemical Substances	DNA-Binding Proteins ; Interleukin Receptor Common gamma Subunit ; Rag2 protein, mouse ; Receptors, Interleukin-4
Language	English
Publishing date	2013-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0071344
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner.

Dasgupta, Preeta / Chapoval, Svetlana P / Smith, Elizabeth P / Keegan, Achsah D

BMC immunology

2011 Volume 12, Page(s) 60

Abstract: Background: CD4+ T helper type 2 (TH2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also ... ...

Abstract	Background: CD4+ T helper type 2 (TH2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also drive alternative activation of macrophages (AAM). However, the precise roles played by the IL-4/IL-13 receptors and STAT6 in inducing AAM protein expression and modulating specific features of airway inflammation are still unclear. Since TH2 differentiation and activation plays a pivotal role in this disease, we explored the possibility of developing an asthma model in mice using T cells that were differentiated in vivo. Results: In this study, we monitored the activation and proliferation status of adoptively transferred allergen-specific naïve or in vivo primed CD4+ T cells. We found that both the naïve and in vivo primed T cells expressed similar levels of CD44 and IL-4. However, in vivo primed T cells underwent reduced proliferation in a lymphopenic environment when compared to naïve T cells. We then used these in vivo generated effector T cells in an asthma model. Although there was reduced inflammation in mice lacking IL-4Rα or STAT6, significant amounts of eosinophils were still present in the BAL and lung tissue. Moreover, specific AAM proteins YM1 and FIZZ1 were expressed by epithelial cells, while macrophages expressed only YM1 in RAG2-/- mice. We further show that FIZZ1 and YM1 protein expression in the lung was completely dependent on signaling through the IL-4Rα and STAT6. Consistent with the enhanced inflammation and AAM protein expression, there was a significant increase in collagen deposition and smooth muscle thickening in RAG2-/- mice compared to mice deficient in IL-4Rα or STAT6. Conclusions: These results establish that transfer of in vivo primed CD4+ T cells can induce allergic lung inflammation. Furthermore, while IL-4/IL-13 signaling through IL-4Rα and STAT6 is essential for AAM protein expression, lung inflammation and eosinophilia are only partially dependent on this pathway. Further studies are required to identify other proteins and signaling pathways involved in airway inflammation.
MeSH term(s)	Adoptive Transfer ; Animals ; Asthma/immunology ; Cells, Cultured ; Complement Pathway, Alternative/genetics ; Disease Models, Animal ; Hyaluronan Receptors/metabolism ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/immunology ; Intercellular Signaling Peptides and Proteins/metabolism ; Lectins/genetics ; Lectins/immunology ; Lectins/metabolism ; Lymphocyte Activation/genetics ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mice, Transgenic ; Pneumonia/genetics ; Pneumonia/immunology ; Pulmonary Eosinophilia/genetics ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; STAT6 Transcription Factor/genetics ; STAT6 Transcription Factor/metabolism ; Signal Transduction/immunology ; Th2 Cells/immunology ; Th2 Cells/metabolism ; Th2 Cells/pathology ; Th2 Cells/transplantation ; beta-N-Acetylhexosaminidases/genetics ; beta-N-Acetylhexosaminidases/immunology ; beta-N-Acetylhexosaminidases/metabolism
Chemical Substances	Hyaluronan Receptors ; Il4ra protein, mouse ; Intercellular Signaling Peptides and Proteins ; Lectins ; Receptors, Cell Surface ; Retnla protein, mouse ; STAT6 Transcription Factor ; Chil3 protein, mouse (EC 3.2.1.52) ; beta-N-Acetylhexosaminidases (EC 3.2.1.52)
Language	English
Publishing date	2011-10-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1471-2172
ISSN (online)	1471-2172
DOI	10.1186/1471-2172-12-60
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Article ; Online: Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner

Keegan Achsah D / Smith Elizabeth P / Chapoval Svetlana P / Dasgupta Preeta

BMC Immunology, Vol 12, Iss 1, p

2011 Volume 60

Abstract: Abstract Background CD4+ T helper type 2 (T H 2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and ... ...

Abstract	Abstract Background CD4+ T helper type 2 (T H 2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also drive alternative activation of macrophages (AAM). However, the precise roles played by the IL-4/IL-13 receptors and STAT6 in inducing AAM protein expression and modulating specific features of airway inflammation are still unclear. Since T H 2 differentiation and activation plays a pivotal role in this disease, we explored the possibility of developing an asthma model in mice using T cells that were differentiated in vivo . Results In this study, we monitored the activation and proliferation status of adoptively transferred allergen-specific naïve or in vivo primed CD4+ T cells. We found that both the naïve and in vivo primed T cells expressed similar levels of CD44 and IL-4. However, in vivo primed T cells underwent reduced proliferation in a lymphopenic environment when compared to naïve T cells. We then used these in vivo generated effector T cells in an asthma model. Although there was reduced inflammation in mice lacking IL-4Rα or STAT6, significant amounts of eosinophils were still present in the BAL and lung tissue. Moreover, specific AAM proteins YM1 and FIZZ1 were expressed by epithelial cells, while macrophages expressed only YM1 in RAG2 -/- mice. We further show that FIZZ1 and YM1 protein expression in the lung was completely dependent on signaling through the IL-4Rα and STAT6. Consistent with the enhanced inflammation and AAM protein expression, there was a significant increase in collagen deposition and smooth muscle thickening in RAG2 -/- mice compared to mice deficient in IL-4Rα or STAT6. Conclusions These results establish that transfer of in vivo primed CD4+ T cells can induce allergic lung inflammation. Furthermore, while IL-4/IL-13 signaling through IL-4Rα and STAT6 is essential for AAM protein expression, lung inflammation and eosinophilia are only partially dependent on this pathway. Further studies are required to identify other proteins and signaling pathways involved in airway inflammation.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Allergy and Immunology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	570
Language	English
Publishing date	2011-10-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation.

Dasgupta, Preeta / Dorsey, Nicolas J / Li, Jiaqi / Qi, Xiulan / Smith, Elizabeth P / Yamaji-Kegan, Kazuyo / Keegan, Achsah D

Science signaling

2016 Volume 9, Issue 433, Page(s) ra63

Abstract: Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 ... ...

Abstract	Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 contribute to allergic lung inflammation. To examine the role of IRS2 in allergic disease, we evaluated the responses of IRS2-deficient (IRS2(-/-)) mice. Unexpectedly, loss of IRS2 resulted in a substantial increase in the expression of a subset of genes associated with the generation of alternatively activated macrophages (AAMs) in response to IL-4 or IL-13 in vitro. AAMs secrete factors that enhance allergic responses and promote airway remodeling. Moreover, compared to IRS2(+/+) mice, IRS2(+/-) and IRS2(-/-) mice developed enhanced pulmonary inflammation, accumulated eosinophils and AAMs, and exhibited airway and vascular remodeling upon allergen stimulation, responses that partially depended on macrophage-intrinsic IRS2 signaling. Both in unstimulated and IL-4-stimulated macrophages, lack of IRS2 enhanced phosphorylation of Akt and ribosomal S6 protein. Thus, we identified a critical inhibitory loop downstream of IRS2, demonstrating an unanticipated and previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling.
Language	English
Publishing date	2016-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aad6724
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Article ; Online: Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6.

Chapoval, Svetlana / Dasgupta, Preeta / Dorsey, Nicolas J / Keegan, Achsah D

Journal of leukocyte biology

2010 Volume 87, Issue 6, Page(s) 1011–1018

Abstract: During the development of immune responses to pathogens, self-antigens, or environmental allergens, naive CD4(+) T cells differentiate into subsets of effector cells including Th1, Th2, and Th17 cells. The differentiation into these subsets is controlled ...

Abstract	During the development of immune responses to pathogens, self-antigens, or environmental allergens, naive CD4(+) T cells differentiate into subsets of effector cells including Th1, Th2, and Th17 cells. The differentiation into these subsets is controlled by specific transcription factors. The activity of these effector cells is limited by nTregs and iTregs, whose differentiation and maintenance are dependent on the transcription factor Foxp3. The regulation of autoimmune diseases mediated by Th1 and Th17 cells by Tregs has been studied and reviewed extensively. However, much less has been presented about the interplay between Tregs and Th2 cells and their contribution to allergic disease. In this perspective, we discuss the regulation of Th2 cells by Tregs and vice versa, focusing on the interplay between the IL-4-activated STAT6/GATA3 pathway and Foxp3.
MeSH term(s)	Animals ; Humans ; Interleukin-4/metabolism ; STAT6 Transcription Factor/metabolism ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/immunology ; Th2 Cells/immunology
Chemical Substances	STAT6 Transcription Factor ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2010-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.1209772
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Article ; Online: Adoptive transfer of IL-4Rα + macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation

Ford Andrew Q / Dasgupta Preeta / Mikhailenko Irina / Smith Elizabeth MP / Noben-Trauth Nancy / Keegan Achsah D

BMC Immunology, Vol 13, Iss 1, p

2012 Volume 6

Abstract: Abstract Background The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα ...

Abstract	Abstract Background The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα expression on both bone marrow-derived and non-bone marrow-derived cells contributed to the severity of allergic lung inflammation. There was a correlation between the number of macrophages expressing the IL-4Rα, CD11b, and IA d , and the degree of eosinophilia in ovalbumin challenged mice. The engagement of the IL-4Rα by IL-4 or IL-13 is able to stimulate the alternative activation of macrophages (AAM). The presence of AAM has been correlated with inflammatory responses to parasites and allergens. Therefore, we hypothesized that IL-4Rα + AAM play an active role in allergic lung inflammation. To directly determine the role of AAM in allergic lung inflammation, M-CSF-dependent macrophages (BMM) were prepared from the bone-marrow of IL-4Rα positive and negative mice and transferred to IL-4RαxRAG2 -/- mice. Wild type TH2 cells were provided exogenously. Results Mice receiving IL-4Rα +/+ BMM showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4Rα -/- BMM. As expected, the eosinophilic inflammation was dependent on the presence of TH2 cells. Furthermore, we observed an increase in cells expressing F4/80 and Mac3, and the AAM marker YM1/2 in the lungs of mice receiving IL-4Rα +/+ BMM. The BAL fluid from these mice contained elevated levels of eotaxin-1, RANTES, and CCL2. Conclusions These results demonstrate that transfer of IL-4Rα + macrophages is sufficient to enhance TH2-driven, allergic inflammation. They further show that stimulation of macrophages through IL-4Rα leads to their alternative activation and positive contribution to the TH2-driven allergic inflammatory response in the lung. Since an increase in AAM and their products has been observed in patients with asthma exacerbations, these results suggest that AAM may be targeted to alleviate exacerbations.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Allergy and Immunology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	333
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Adoptive transfer of IL-4Rα+ macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation.

Ford, Andrew Q / Dasgupta, Preeta / Mikhailenko, Irina / Smith, Elizabeth M P / Noben-Trauth, Nancy / Keegan, Achsah D

BMC immunology

2012 Volume 13, Page(s) 6

Abstract: Background: The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα ... ...

Abstract	Background: The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα expression on both bone marrow-derived and non-bone marrow-derived cells contributed to the severity of allergic lung inflammation. There was a correlation between the number of macrophages expressing the IL-4Rα, CD11b, and IA(d), and the degree of eosinophilia in ovalbumin challenged mice. The engagement of the IL-4Rα by IL-4 or IL-13 is able to stimulate the alternative activation of macrophages (AAM). The presence of AAM has been correlated with inflammatory responses to parasites and allergens. Therefore, we hypothesized that IL-4Rα⁺ AAM play an active role in allergic lung inflammation. To directly determine the role of AAM in allergic lung inflammation, M-CSF-dependent macrophages (BMM) were prepared from the bone-marrow of IL-4Rα positive and negative mice and transferred to IL-4RαxRAG2(-/-) mice. Wild type TH2 cells were provided exogenously. Results: Mice receiving IL-4Rα(+/+) BMM showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4Rα(-/-) BMM. As expected, the eosinophilic inflammation was dependent on the presence of TH2 cells. Furthermore, we observed an increase in cells expressing F4/80 and Mac3, and the AAM marker YM1/2 in the lungs of mice receiving IL-4Rα(+/+) BMM. The BAL fluid from these mice contained elevated levels of eotaxin-1, RANTES, and CCL2. Conclusions: These results demonstrate that transfer of IL-4Rα + macrophages is sufficient to enhance TH2-driven, allergic inflammation. They further show that stimulation of macrophages through IL-4Rα leads to their alternative activation and positive contribution to the TH2-driven allergic inflammatory response in the lung. Since an increase in AAM and their products has been observed in patients with asthma exacerbations, these results suggest that AAM may be targeted to alleviate exacerbations.
MeSH term(s)	Adoptive Transfer ; Animals ; Bone Marrow Transplantation ; Bronchoalveolar Lavage Fluid ; Chickens ; Disease Models, Animal ; Eosinophils/metabolism ; Eosinophils/pathology ; Humans ; Hypersensitivity/complications ; Hypersensitivity/pathology ; Interleukin-4 Receptor alpha Subunit/metabolism ; Lung/immunology ; Lung/pathology ; Macrophage Activation/immunology ; Macrophages/metabolism ; Macrophages/pathology ; Macrophages/transplantation ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Ovalbumin/immunology ; Phenotype ; Pneumonia/complications ; Pneumonia/pathology ; Staining and Labeling ; Th2 Cells/immunology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Interleukin-4 Receptor alpha Subunit ; Tumor Necrosis Factor-alpha ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2012-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2041500-X
ISSN	1471-2172 ; 1471-2172
ISSN (online)	1471-2172
ISSN	1471-2172
DOI	10.1186/1471-2172-13-6
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