Cutting Edge: Deficiency of Macrophage Migration Inhibitory Factor Impairs Murine Airway Allergic Responses

Wang, Bing; Huang, Xiaozhu; Wolters, Paul J.; Sun, Jiusong; Kitamoto, Shiro; Riese, Richard J.; Leng, Lin; Chapman, Harold A.; David, John R.; Bucala, Richard; Shi, Guo Ping

doi:10.4049/jimmunol.177.9.5779

Cited by 29 publications

(36 citation statements)

References 28 publications

(36 reference statements)

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“…Consistent with this data, MIF levels were significantly lower in colonic tissue and sera in TRX-Tg mice in a mouse model of acute DSS-induced colitis [32]. Recent studies indicate that MIF plays an essential role in the pathogenesis of allergic airway inflammation [3][4][5][6]. Upon allergen sensitization and challenge, mice lacking MIF exhibit reduced AHR, tissue eosinophilia, and mucus metaplasia with concomitant decreases in levels of eotaxin and IL-13 in BALF.…”

Section: Discussionsupporting

confidence: 72%

“…Recent studies suggest that MIF may play a key role in the pathogenesis of airway inflammation [3][4][5][6]. Therefore, we next examined the lungs of TRX-Tg and WT mice for differences in MIF expression in our model of asthma.…”

Section: Reduced Production Of Mif By Lung Epithelial Cells From Trx-mentioning

confidence: 99%

“…Although eosinophils are the predominant cell type in the lung of asthmatic subjects that mediate tissue damage, allergen specific Th2 cells generated in the secondary lymphoid organs and migrated into the lung are central to the pathogenesis of asthma via secretion of IL-4 and IL-5 contributing to mobilization of eosinophils and IL-9 and IL-13 contributing to AHR [2]. Additionally, recent studies have implicated MIF produced by lung epithelial cells, macrophages, and mast cells as an essential factor in the pathogenesis of asthma [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Torii

Wang

et al. 2010

Eur J Immunol

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Oxidative stress plays an important role in the pathogenesis of asthma via the upregulation of local inflammatory mediators and/or promoting Th2-skewing during Ag sensitization. Thioredoxin (TRX), a 12 kDa redox-active protein with antioxidative property, has been recently shown to play a protective role in various inflammatory diseases. Using a mouse model of asthma, we show here that IL-13 and eotaxin production are decreased in TRX-Tg mice leading to reduced eosinophils recruitment and mucus metaplasia. The reduction in airway inflammation occurs without the attenuation of systemic Th2 immunity in that comparable levels of Th2-type cytokines and Ig were detected in LN and serum, respectively, from TRX-Tg and WT mice. Likewise, CD4 1 T cells from both strains of mice developed similar Th1 and Th2 responses in vitro. Asthmatic lungs of TRX-Tg and WT mice contained similar amounts of GATA-3 1 and Foxp3 1 T cells. Finally, production of MIF, an upstream modulator of airway inflammation, was significantly reduced in the lungs of TRX-Tg mice. Our data suggest that TRX suppresses airway inflammation by inhibiting MIF production thereby limiting the downstream recruitment of eosinophils to the lung independently of modulating systemic Th1/Th2 immunity.

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Section: Discussionsupporting

confidence: 72%

Section: Reduced Production Of Mif By Lung Epithelial Cells From Trx-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Torii

Wang

et al. 2010

Eur J Immunol

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“…Another study using a protocol of immunization with OVA and alum to induce allergic rhinitis demonstrated that MIF -/-mice have reduced eosinophil inflammation and mucus metaplasia, but develop a robust Th2 response [44]. Recent studies also revealed a critical role of MIF on AHR, mucus production and lung inflammation in a model of asthma [34,45]. In these studies, however, using slightly different protocols to induce allergic inflammation endogenous MIF was considered essential for Th2 differentiation and IgE production induced by OVA.…”

mentioning

confidence: 99%

“…It has been proposed that the mechanism responsible for the reduced splenic T cell activation observed on MIF -/-mice upon OVA immunization involves a defect on antigen presentation [34,45]. In fact, the ability to activate T cells in vitro is compromised on macrophages and mast cells but not on DC obtained from MIF -/-mice [45]. It is unclear whether these differences on activation of T cells from spleen and lymph node is related to a preferential involvement of non-DC as APC in the spleen versus DC on draining lymph nodes.…”

mentioning

confidence: 99%

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

et al. 2007

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Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF -/-mice occurs regardless of high concentrations of IL-4 in the lung and OVAspecific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF -/-mice compared to WT, but were reduced in the spleen of MIF -/-, thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4 + cells with anti-CD3 antibody demonstrated that MIF -/-cells produced increased amounts of IFN-c and IL-4 compared to WT CD4 + cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma. IntroductionAllergic asthma is a disorder characterized by chronic lung inflammation, reversible airway obstruction and increases in airway hyper-responsiveness (AHR) to nonspecific stimuli. Several studies have provided compelling evidences that the lung infiltrating leukocytes and the proinflammatory mediators they produce initiate cellular damage, amplify the immune response, cause airway physiological changes and tissue remodeling [1]. The airway inflammation of asthma has a predominance of Th2 CD4 + lymphocytes, eosinophils and mast cells infiltrating the lung interstitium. Several studies indicate the existence of a mechanism dependent on IL-5 and eosinophils that induce pulmonary damage and intensify AHR [3][4][5]. In other studies, however, the induction of AHR was observed despite the absence of infiltrating eosinophils, suggesting dissociation between these phenomena [6][7][8][9][10]. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule and critical mediator of innate and acquired immune responses [11,12]. Pre-formed MIF protein is present in many cell types and is released in response to different stimuli, such as infection and cytokine stimulation [12]. MIF exhibits several proinflammatory functions, including the induction of TNF-a, IL-1 and NO release from macrophages, and the production of arachidonic acid and eicosanoids through the induction of phospholipase A 2 and cyclooxygenase [13,14]. A unique property of MIF is its secretion by immune cells in response to physiological increase in glucocorticoid levels. Once released, MIF can counterregulate the anti-inflammatory effects of steroids on cyt...

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Mast Cells in Lung Inflammation

Moiseeva

Bradding

2011

Mast Cell Biology

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Mast cells play an important role in the lung in both health and disease. Their primary role is to initiate an appropriate program of inflammation and repair in response to tissue damage initiated by a variety of diverse stimuli. They are important for host immunity against bacterial infection and potentially in the host immune response to non small cell lung cancer. In situations of ongoing tissue damage, the sustained release of numerous pro-inflammatory mediators, proteases and cytokines, contributes to the pathophysiology of lung diseases such as asthma and interstitial lung disease. A key goal is the development of treatments which attenuate adverse mast cell function when administered chronically to humans in vivo. Such therapies may offer a novel approach to the treatment of many life-threatening diseases.

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Cutting Edge: Deficiency of Macrophage Migration Inhibitory Factor Impairs Murine Airway Allergic Responses

Cited by 29 publications

References 28 publications

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

Mast Cells in Lung Inflammation

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