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

Dasgupta, Preeta; Keegan, Achsah

doi:10.1159/000336025

Cited by 41 publications

(37 citation statements)

References 151 publications

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“…In an ovalbumin (OVA)-induced allergic asthma mouse model, in which M2 macrophages play a critical role as shown before 7,43,44 , we found that TSC1KO mice were resistant to OVA-induced asthma as determined by reduced pathological changes, significantly less infiltration by leukocytes and eosinophils in the bronchoalveolar lavage fluid (BALF) of TSC1KO mice than that in WT mice after OVA challenge (Fig. 6e-h).…”

Section: Sensitivity Of Tsc1ko Mice To M1 and M2-releated Diseasessupporting

confidence: 64%

TSC1 controls macrophage polarization to prevent inflammatory disease

et al. 2014

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Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-b pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

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Section: Sensitivity Of Tsc1ko Mice To M1 and M2-releated Diseasessupporting

confidence: 64%

TSC1 controls macrophage polarization to prevent inflammatory disease

et al. 2014

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“…Although it is well known that IL-4 is produced by antigen-specific Th2 lymphocytes, it can also be produced by cells of the innate immune system such as mast cells, basophils, eosinophils, macrophages, and innate lymphoid-like cells (or nuocytes). Early production of Th2 cytokines IL-4 and IL-13 by innate cells is thought to be important for the initiation phase of Th2-dominant inflammation (9). However, ECs do not express or produce IL-4; therefore, endogenous IL-4 is not required for EC apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension

Yamaji-Kegan

Takimoto

Zhang

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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RA. Hypoxia-induced mitogenic factor (FIZZ1/RELM␣) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELM␣) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH. endothelial apoptosis; T-helper type 2 inflammation; human resistin PULMONARY HYPERTENSION (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right-sided heart failure. It is associated with significant morbidity and mortality. Despite major advances in diagnosis and treatment of this disease over the last several decades, the underlying mechanisms of PH remain enigmatic. In humans, severe pulmonary arterial hypertension (PAH, idiopathic PH) is characterized by plexiform lesions that contain phenotypically altered pulmonary smooth muscle and endothelial cells (ECs) (56). Evidence suggests that early EC apoptosis may trigger both degenerative and reactive proliferative events that result in the pulmonary vascular pathology of PH (25). Failure to stop the initial repair response could result in pathophysiological vascular remodeling, such as that which occurs during PH (25). Strong circumstantial clinical evidence supports an immune pathogenesis of PH, but whether the immunological features are a cause or consequence of PH is unknown. It has been shown that vascular endothelial growth factor (VEGF) receptor (VEGFR) blockade with Su...

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“…Macrophages also have key roles in lung disease. For example in asthma, recent studies show that M2 macrophages are not just bystanders but also active players in orchestrating allergic lung disease [16]. During chronic obstructive pulmonary disease, macrophage subsets develop in response to cigarette smoke exposure [17].…”

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confidence: 99%