The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation

Dasgupta, Preeta; Dorsey, Nicolas; Li, Jiaqi; Qi, Xiulan; Smith, E. L.; Yamaji-Kegan, Kazuyo; Keegan, Achsah

doi:10.1126/scisignal.aad6724

Cited by 20 publications

(28 citation statements)

References 66 publications

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“…Surprisingly, it was found that mice homozygous for the IL‐4Rα‐F497 mutation exhibited enhanced allergic inflammation, including IgE production, airway hyperresponsiveness, eosinophilic inflammation and mucus production, suggesting a significant contribution of this pathway to the regulation of allergic inflammation in vivo. A similar phenotype of enhanced airway inflammation was also noted in IRS2 –/– mice, implicating IRS2, which is the differentially expressed in hematopoietic cells vs IRS1, in the negative regulatory function of IL‐4Rα‐Y497 . Thus, the precise role of this pathway in modulating the allergic response remains to be fully delineated (Figure ).…”

Section: Il‐4rα Signalling and Mechanism Of Actionmentioning

confidence: 73%

Mechanisms of Dupilumab

Harb

Chatila

2019

Clin Experimental Allergy

313

241

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The Th2 cytokines interleukin 4 (IL‐4) and IL‐13 and the heterodimeric IL‐4 receptor (IL‐4R) complexes that they interact with play a key role in the pathogenesis of allergic disorders. Dupilumab is a humanized IgG4 monoclonal antibody that targets the IL‐4 receptor alpha chain (IL‐4Rα), common to both IL‐4R complexes: type 1 (IL‐4Rα/γc; IL‐4 specific) and type 2 (IL‐4Rα/IL‐13Rα1; IL‐4 and IL‐13 specific). In this review, we detail the current state of knowledge of the different signalling pathways coupled to the IL‐4R complexes and examine the possible mechanisms of Dupilumab action and survey its clinical efficacy in different allergic disorders. The development of Dupilumab and the widening spectrum of its clinical applications is relevant to the current emphasis on precision medicine approaches to the blockade of pathways involved in allergic diseases.

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Section: Il‐4rα Signalling and Mechanism Of Actionmentioning

confidence: 73%

Mechanisms of Dupilumab

Harb

Chatila

2019

Clin Experimental Allergy

313

241

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“…Indeed, two of four M2 genes were enhanced with p70S6K inhibition, indicating a greater complexity to regulation of M2 gene expression than anticipated. Many M2 genes share common activating and inhibitory pathways (39,40) and can be AKT-dependent or -independent (41). For example, studies of macrophage polarization using macrophages derived from Tsc1 (16, 17)-, Raptor (42)-, and Rictor (16, 42)-deficient mice have con- 1, IL-4 can bind two kinds of IL-4 receptor complexes on monocyte-macrophages, type I (shown here) and type II.…”

Section: Discussionmentioning

confidence: 99%

The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2

Warren

Fang

Gowda

et al. 2016

Journal of Biological Chemistry

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Edited by Luke O'NeillLung M2 macrophages are regulators of airway inflammation, associated with poor lung function in allergic asthma. Previously, we demonstrated that IL-4-induced M2 gene expression correlated with tyrosine phosphorylation of the insulin receptor substrate-2 (IRS-2) in macrophages. We hypothesized that negative regulation of IRS-2 activity after IL-4 stimulation is dependent upon serine phosphorylation of IRS-2. Herein, we describe an inverse relationship between tyrosine phosphorylation (Tyr(P)) and serine phosphorylation (Ser(P)) of IRS-2 after IL-4 stimulation. Inhibiting serine phosphatase activity increased Ser(P)-IRS-2 and decreased Tyr(P)-IRS-2 leading to reduced M2 gene expression (CD200R, CCL22, MMP12, and TGM2). We found that inhibition of p70S6K, downstream of TORC1, resulted in diminished Ser(P)-IRS-2 and prolonged Tyr(P)-IRS-2 as well. Inhibition of p70S6K increased expression of CD200R and CCL22 indicating that p70S6K negatively regulates some, but not all, human M2 genes. Knocking down GRB10, another negative regulatory protein downstream of TORC1, enhanced both Tyr(P)-IRS-2 and increased expression of all four M2 genes. Furthermore, GRB10 associated with IRS-2, NEDD4.2 (an E3-ubiquitin ligase), IL-4R␣, and ␥C after IL-4 stimulation. Both IL-4R␣ and ␥C were ubiquitinated after 30 min of IL-4 treatment, suggesting that GRB10 may regulate degradation of the IL-4 receptor-signaling complex through interactions with NEDD4.2. Taken together, these data highlight two novel regulatory proteins that could be therapeutically manipulated to limit IL-4-induced IRS-2 signaling and polarization of M2 macrophages in allergic inflammation.Both genetic and environmental factors influence the onset and exacerbation of allergic asthma, which remains one of the most costly, non-communicable diseases of the human population. Allergic inflammation is characterized by airway hyperreactivity, type 2 cytokines (IL-4, -5, and -13), IgE, and the overproduction of mucus in the lung (1-3). Macrophages present at the site of allergic inflammation can be polarized by Th2-cytokines to become "alternatively activated" or M2 macrophages. In addition, the abundance of M2 macrophages in the lungs of asthmatics correlates with symptom severity (4 -6). As M2 macrophage polarization is dependent upon IL-4 stimulation, this cytokine and its signaling pathways represent excellent targets for asthma therapies.Our previous work has identified IL-4 signaling through the type I IL-4 receptor complex and activation of insulin receptor substrate 2 (IRS-2) 2 as important for the degree of polarization of M2 macrophages (7). IL-4 binds first to the IL-4R␣ chain with high affinity followed by recruitment of the common ␥ chain (IL-2R␥ or ␥C) to create a functional type I receptor. Assembly of this receptor complex leads to recruitment and phosphorylation of the JAK1 and -3 proteins followed by robust, yet transient, tyrosine phosphorylation of IRS-2 and STAT6. Phosphorylated STAT6 homodimerizes and translocates to the nucleus, ...

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“…In contrast, macrophages that lack IGF1R acquire a more inflammatory phenotype in response to proinflammatory stimuli (4,6). However, IRS2, which mediates both insulin and IGF1 signaling, suppresses alternative activation of macrophages (7). In addition, glucose, insulin, and palmitate treatment of human monocyte-derived macrophages results in a metabolically activated phenotype, a distinct M1 phenotype that is characteristic for proinflammatory ATMs found in obesity (8).…”

mentioning

confidence: 99%

Insulin Resistance in Macrophages Alters Their Metabolism and Promotes an M2-Like Phenotype

Ieronymaki

Theodorakis

Lyroni

et al. 2019

The Journal of Immunology

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Obesity and insulin resistance influences metabolic processes, but whether it affects macrophage metabolism is not known. In this study, we demonstrate that chronic exposure of macrophages to insulin either in culture or in vivo in diet-induced, glucose-intolerant mice rendered them resistant to insulin signals marked by failure to induce Akt2 phosphorylation. Similarly, macrophages lacking Akt2 or IGF1 receptor were also resistant to insulin signals. Insulin-resistant macrophages had increased basal mTORC1 activity, possessed an M2-like phenotype, and reduced LPS responses. Moreover, they exhibited increased glycolysis and increased expression of key glycolytic enzymes. Inhibition of mTORC1 reversed the M2-like phenotype and suppressed glycolysis in insulin-resistant macrophages. In the context of polymicrobial sepsis, mice harboring insulin-resistant macrophages exhibited reduced sepsisinduced lung injury. Thus, macrophages obtain resistance to insulin characterized by increased glycolysis and a unique M2-like phenotype, termed M-insulin resistant, which accounts for obesity-related changes in macrophage responses and a state of trained immunity.

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The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation

Cited by 20 publications

References 66 publications

Mechanisms of Dupilumab

Mechanisms of Dupilumab

The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2

Insulin Resistance in Macrophages Alters Their Metabolism and Promotes an M2-Like Phenotype

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