Type I IL-4Rs Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages

Heller, Nicola; Qi, Xiulan; Junttila, Ilkka; Shirey, Kari Ann; Vogel, Stefanie N.; Paul, William E.; Keegan, Achsah

doi:10.1126/scisignal.1164795

Cited by 146 publications

(212 citation statements)

References 92 publications

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“…IL-4 acts through activation of the Jak/STAT signaling pathway and inhibits release of pro-inflammatory cytokines by Mo. 66 Our data demonstrate that IL-4 also rapidly downregulates the expression of CX 3 CR1 mRNA, accompanied by a decrease in the cell surface expression of this receptor. The latter may somewhat precede that of the mRNA, suggesting that regulation at the translation level may also be involved.…”

Section: Cr1 Gene Expression In Mos Macs and Dcsmentioning

confidence: 60%

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

et al. 2014

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Circulating monocytes (Mos) may continuously repopulate macrophage (MAC) or dendritic cell (DC) populations to maintain homeostasis. MACs and DCs are specialized cells that play different and complementary immunological functions. Accordingly, they present distinct migratory properties. Specifically, whereas MACs largely remain in tissues, DCs are capable of migrating from peripheral tissues to lymphoid organs. The aim of this work was to analyze the expression of the fractalkine receptor (CX 3 CR1) during the monocytic differentiation process. Freshly isolated Mos express high levels of both CX 3 CR1 mRNA and protein. During the Mo differentiation process, CX 3 CR1 is downregulated in both DCs and MACs. However, MACs showed significantly higher CX 3 CR1 expression levels than did DC. We also observed an antagonistic CX 3 CR1 regulation by interferon (IFN)-c and interleukin (IL)-4 during MAC activation through the classical and alternative MAC pathways, respectively. IFN-c inhibited the loss of CX 3 CR1, but IL-4 induced it. Additionally, we demonstrated an association between CX 3 CR1 expression and apoptosis prevention by soluble fractalkine (sCX 3 CL1) in Mos, DCs and MACs. This is the first report demonstrating sequential and differential CX 3 CR1 modulation during Mo differentiation. Most importantly, we demonstrated a functional link between CX 3 CR1 expression and cell survival in the presence of sCX 3 CL1.

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Section: Cr1 Gene Expression In Mos Macs and Dcsmentioning

confidence: 60%

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

et al. 2014

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“…We (63) have demonstrated previously that IL-4-stimulated migration of AEC requires signaling from the receptor to IRS-1 and IRS-2 such that signaling via STAT6 is irrelevant to migration. One recent study suggests that only type I receptor, ␥c-dependent signaling induced efficient activation of IRS-2 (18). Regulation of receptor subunit expression then may alter the activation of effector pathways and thus provide another opportunity for fine-tuning epithelial cell responsiveness in a given state.…”

Section: Discussionmentioning

confidence: 99%

Expression of IL-4/IL-13 receptors in differentiating human airway epithelial cells

White

Martin

Stern

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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and IL-13 elicit several important responses in airway epithelium including chemokine secretion and mucous secretion that may contribute to airway inflammation, cell migration, and differentiation. These cytokines have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes. These receptors are variably described in epithelial cells, and the relative expression, localization, and function of these receptors in differentiated and repairing epithelial cells are not clear. We examined IL-4/IL-13 receptor expression and localization in primary airway epithelial cells collected from normal human lungs and grown under conditions yielding both undifferentiated and differentiated cells inclusive of basal, goblet, and ciliated cell phenotypes. Gene expression of the IL-4R␣, IL-2R␥c, IL-13R␣1, and IL-13R␣2 receptor subunits increased with differentiation, but different patterns of localization and protein abundance were seen for each subunit based on both differentiation and the cell subtypes present. Increased expression of receptor subunits observed in more differentiated cells was associated with more substantial functional responses to IL-4 stimulation including increased eotaxin-3 expression and accelerated migration after injury. We demonstrate substantial differences in IL-4/IL-13 receptor subunit expression and responsiveness to IL-4 based on the extent of airway epithelial cell differentiation and suggest that these differences may have functional consequences in airway inflammation.interleukin-4; interleukin-13; eotaxin-3; migration THE AIRWAY EPITHELIUM is both a target of inflammatory and physical insults and an effector of ongoing airway inflammation (2,20,31,37,45). As such, it plays a critical role in diseases such as chronic asthma. Epithelial injury leads to release of chemokines such as 8,13), GM-CSF (13, 42), and eotaxin (65) that then stimulate inflammatory cell infiltration. Injury also leads to disordered regulation of submucosal myofibroblasts (19) and subsequent subbasement membrane fibrinogenesis (40). Persistent epithelial injury (31,39,56) is a characteristic part of airway remodeling (9) in asthma.Activated lymphocytes are a prominent feature in asthmatic airways (5,6,32). BAL fluid obtained from asthmatics is enriched in both IL-4 (50) and IL-13 (21, 22) but not IFN-␥ (50), indicating the presence of T helper type 2 (Th2) subclass CD4 ϩ cells. Both IL-4 and IL-13 may stimulate epithelial cells to produce chemokines such as eotaxin-3 (28, 55, 65), GM-CSF (42), 28), and RANTES (17,46) and growth factors such as transforming growth factor-␤ (TGF-␤) (50, 57) and the EGF receptor-binding factor, TGF-␣ (4). Overexpression of either IL-4 or IL-13 in murine airways elicits inflammation, subepithelial fibrosis, and mucous cell metaplasia (49, 67).IL-4 and IL-13 have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes (43). IL-4 can bind to two distinct receptors: the type I receptor consisting of the...

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“…We elected to use IL-4 treatment instead of IL-13, which can also signal through a macrophage IL-4 receptor to promote M2 protein expression, because IL-4 can induce more robust expression of M2 genes (25) and may be less likely to induce B: experimental design for Treg depletion in Foxp3 DTR mice using intraperitoneal injection of diphtheria toxin (DT). All Foxp3 DTR mice received DT to deplete Tregs and either IL-4 or PBS treatment following intratracheal LPS.…”

Section: Discussionmentioning

confidence: 99%

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming

D’Alessio

Craig

Singer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Type I IL-4Rs Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages

Cited by 146 publications

References 92 publications

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

Expression of IL-4/IL-13 receptors in differentiating human airway epithelial cells

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming

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