More alternative activation of macrophages in lungs of asthmatic patients

Melgert, Barbro N.; Hacken, Nick H. T. ten; Rutgers, Bea; Timens, Wim; Postma, Dirkje S.; Hylkema, Machteld N.

doi:10.1016/j.jaci.2010.10.045

Cited by 157 publications

(139 citation statements)

References 9 publications

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“…Th2 cells and IL-4-driven M2 polarization both play active roles in the pathogenesis of allergic asthma 49 . TSC1KO mice were resistant to OVA challenge-induced allergic asthma.…”

Section: Discussionmentioning

confidence: 99%

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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“…Th2 cells and IL-4-driven M2 polarization both play active roles in the pathogenesis of allergic asthma 49 . TSC1KO mice were resistant to OVA challenge-induced allergic asthma.…”

Section: Discussionmentioning

confidence: 99%

TSC1 controls macrophage polarization to prevent inflammatory disease

et al. 2014

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“…Allergy is driven by Th2 cells and products and is associated with M2 polarization of macrophages (72,73). IL-4-inducible chemokines acting on CCR4 (e.g., CCL22) have also been reported to promote skewing of macrophage function (74).…”

Section: Allergymentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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(Retnla, Fizz1), and chitinase 3-like 3 (Chi3l3, Ym1) (14). IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype (4,15,16). STAT-mediated activation of macrophages is regulated by members of the SOCS family. IL-4 and IFN-γ, the latter in concert with TLR stimulation, upregulate SOCS1 and SOCS3, which in turn inhibit the action of STAT1 and STAT3, respectively (17,18).Downstream of, or in parallel with, the IRF/STAT/SOCS pathway, a panel of transcription factors orchestrates polarized macrophage activation. The nuclear receptors PPARγ (19) and PPARδ (20,21) control distinct subsets of genes associated with M2 macrophage activation and oxidative metabolism (Figure 1). Interestingly, STAT6 coordinates and synergizes with both PPARγ (22) and Krüppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function (23, 24). KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. KLF2 regulates macrophage activation by inhibiting NF-κB/ HIF-1α activities (25). IL-4 also induces c-Myc activity in human macrophages (26), which controls genes of M2 activation (Scarb1, Alox15, and Mrc1) as well as STAT6 and PPARγ activation (26).TLR engagement leads to NF-κB activation and production of inflammatory mediators (27) associated with M1 macrophages. However, NF-κB activation also activates a genetic program essential for resolution of inflammation (28) and for M2 polarization of tumor-associated macrophages (TAMs) (29). Moreover, induction of p50 NF-κB homodimers is essential for M2 polarization in vitro and in vivo (30). The hypoxia-inducible factors HIF-1α and HIF-2α are expressed differentially in M1- and M2-polarized macrophages (31) and regulate inducible NOS2 (M1) and arginase 1 (M2), respectively. Figure 1Mechanisms of macrophage polarization. The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage-polarizing pathways is also indicated. The balance between activation of STAT1 and STAT3/STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, associated with immune suppression and tumor progression. PPARγ and PPARδ control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF4 and KLF2 participate in the promotion of M2 macrophage functions by cooperating with STAT6 and suppressing the NF-κB/HIF-1α-dependent transcription, respectively. IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 polarization. IL-10 promotes M2 polarization through the induction of p50 NF-κB homodimer, c-Maf, and STAT3 activities. Epigenetic ...

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“…M2 macrophages play a role in asthma (19)(20)(21). We also demonstrated that OVA sensitization and challenge increases alternative activation of BAL macrophages (1).…”

Section: Original Research Ova-sensitization and Challenge Induces M2mentioning

confidence: 95%

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Chung¹,

Hong

Lei³

et al. 2015

Am J Respir Cell Mol Biol

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Rhinovirus (RV) causes asthma exacerbations. Previously, we showed that adherent bronchoalveolar cells from allergen-treated mice produce IL-13 when stimulated with RV ex vivo, implicating cells of the monocyte/macrophage lineage in viral-induced airway inflammation. In this study, we hypothesized that RV infection of allergen-treated mice results in IL-13 production by CD11b1 exudative macrophages in vivo. We sensitized and challenged BALB/c mice with ovalbumin (OVA), after which mice were inoculated with RV or sham HeLa cell lysate. After 1 day, lungs were harvested, and cell suspensions were analyzed by flow cytometry. We repeated this process in IL-13 reporter mice, CD11b-DTR mice in which diphtheria toxin selectively depletes CD11b1 cells, and chemokine receptor 2 (CCR2) null mice. We found that lungs of mice infected with RV alone showed increases in CD451, CD681, F4/801, Ly6C1, and CD11b high cells, indicating an influx of inflammatory monocytes and exudative macrophages. The combination of OVA and RV had synergistic effects on the exudative macrophage number. However, CD11b1 cells from OVA-treated, RV-infected mice showed M2 polarization, including expression of CD206 and CD301 and production of IL-13. Similar results were obtained in IL-13 reporter mice. Diphtheria toxin depleted CD11b1, IL-13-producing cells in OVA-treated, RV-infected, CD11b-DTR mice, decreasing airway inflammation and responsiveness. CD11b1, Ly6C1 cells were reduced in CCR2 knockout mice. We conclude that, in contrast to naive mice, RV infection of mice with allergic airways disease induces an influx of IL-13-producing CD11b1 exudative macrophages bearing M2 macrophage markers. This finding further implicates alternatively activated macrophages in RV-induced asthma exacerbations.

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More alternative activation of macrophages in lungs of asthmatic patients

Cited by 157 publications

References 9 publications

TSC1 controls macrophage polarization to prevent inflammatory disease

TSC1 controls macrophage polarization to prevent inflammatory disease

Macrophage plasticity and polarization: in vivo veritas

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

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