Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins

McCormick, Sarah; Heller, Nicola

doi:10.3389/fimmu.2015.00549

Cited by 59 publications

(74 citation statements)

References 218 publications

(218 reference statements)

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“…In addition, species-specific differences in SOCS function may account for our differing results (37). Overall, our findings were further supported by the observation that knocking down SOCS1 expression resulted in an increase in expression in all the M2-associated genes we measured in human monocytes, as well as mouse macrophages.…”

Section: Socs1 Regulates Il-4-induced Irs-2 Signaling In Human Monocytessupporting

confidence: 81%

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Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

McCormick¹,

Gowda²,

Fang³

et al. 2016

Journal of Biological Chemistry

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Allergic asthma is a chronic lung disease initiated and driven by Th2 cytokines IL-4/-13. In macrophages, IL-4/-13 bind IL-4 receptors, which signal through insulin receptor substrate (IRS)-2, inducing M2 macrophage differentiation. M2 macrophages correlate with disease severity and poor lung function, although the mechanisms that regulate M2 polarization are not understood. Following IL-4 exposure, suppressor of cytokine signaling (SOCS)1 is highly induced in human monocytes. We found that siRNA knockdown of SOCS1 prolonged IRS-2 tyrosine phosphorylation and enhanced M2 differentiation, although siRNA knockdown of SOCS3 did not affect either. By co-immunoprecipitation, we found that SOCS1 complexes with IRS-2 at baseline, and this association increased after IL-4 stimulation. Because SOCS1 is an E3 ubiquitin ligase, we examined the effect of proteasome inhibitors on IL-4-induced IRS-2 phosphorylation. Proteasomal inhibition prolonged IRS-2 tyrosine phosphorylation, increased ubiquitination of IRS-2, and enhanced M2 gene expression. siRNA knockdown of SOCS1 inhibited ubiquitin accumulation on IRS-2, although siRNA knockdown of SOCS3 had no effect on ubiquitination of IRS-2. Monocytes from healthy and allergic individuals revealed that SOCS1 is induced by IL-4 in healthy monocytes but not allergic cells, whereas SOCS3 is highly induced in allergic monocytes. Healthy monocytes displayed greater ubiquitination of IRS-2 and lower M2 polarization than allergic monocytes in response to IL-4 stimulation. Here, we identify SOCS1 as a key negative regulator of IL-4-induced IRS-2 signaling and M2 differentiation. Our findings provide novel insight into how dysregulated expression of SOCS increases IL-4 responses in allergic monocytes, and this may represent a new therapeutic avenue for managing allergic disease.Allergic asthma is an immune disorder characterized by elevation of total and specific IgE and infiltration of monocytes, lymphocytes, mast cells, eosinophils, and basophils in the lungs that causes inflammation and wheezing, cough, and dyspnea (1-4). A complex interplay of genetic and environmental factors contributes to the onset and maintenance of these diseases. Mechanistically, it is known that cytokines secreted from Th2 cells, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, have a pivotal role in dictating the pathology of allergic disease (1, 2, 5, 6). The pathways by which IL-4 and IL-13 exert their biological effects have been a major focus of research and development of therapeutics to block their action through type I and II IL-4 receptors. Previously, we showed that in macrophages, IL-4 engagement of the type I IL-4 receptor resulted in robust tyrosine phosphorylation of insulin receptor substrate (IRS)-2, recruitment of p85 regulatory subunit of PI3K and GRB2, and strong induction of a subset of hallmark M2, also known as M(IL-4) (7), macrophage genes (8, 9). In contrast, IL-13 binding to the type II receptor resulted in only modest IRS-2 phosphorylation. Increasing the concentration of IL-13 did n...

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Section: Socs1 Regulates Il-4-induced Irs-2 Signaling In Human Monocytessupporting

confidence: 81%

“…The amount of expression and activity of different SOCS family members can reciprocally regulate the outcome of polarization of macrophages, T-cells, and dendritic cells (37)(38)(39)(40)(41). SOCS3 regulates development of M1 cells (42)(43)(44), and SOCS1 regulates polarization to the M2 phenotype (45).…”

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confidence: 99%

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

McCormick¹,

Gowda²,

Fang³

et al. 2016

Journal of Biological Chemistry

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“…SOCS1 is not only induced by cytokine activation of the JAK/STAT pathway but also acts as a negative feedback regulator to inhibit JAK signaling [13]. It has been proven that SOCS proteins can better control inflammation during ischemic stroke and that SOCS1 expression in the brain could be a treatment option for acute brain injuries, including stroke and trauma [15]. Based on this evidence, our study aims to elucidate how to manipulate the SOCS1-JAK2-STAT3 signaling pathway to protect neurons, which could provide a new target for the clinical treatment of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

Wang

Qiao

Liu

et al. 2017

Cell Physiol Biochem

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Background: The present study aims to investigate the protective effects of the SOCS1-JAK2-STAT3 signaling pathway on neurons in a rat model of ischemic stroke. Methods: Our study was conducted using an ischemic stroke rat model. After the microglia were extracted, 40 neonatal Sprague-Dawley (SD) rats were assigned into the blank, AG490, model and negative control (NC) groups. The neurological function of all the rats was evaluated. Histopathological changes were observed. qRT-PCR and western blotting were applied to measure the expression of genes and proteins in the SOCS1-JAK2-STAT3 signaling pathway and related to apoptosis. The TUNEL assay was conducted to calculate the cellular morphology and apoptosis of neuronal cells. Cell viability was detected using the MTT assay. In addition, immunoassays were used to measure the content of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) as well as the levels of oxidative stress. Results: Compared with the blank group, the model and NC groups showed higher neurological function scores—the cytoplasm of the neurons were cavitated, the organelles were reduced with unclear margins, some of the neurons were necrotic, and apoptosis was increased. In addition, the NC and model groups exhibited decreased cell viability, lower mRNA and protein expression of SOCS1 SOCS3 and bcl-2 and reduced SOD and GSH levels but higher mRNA and protein expression levels of AK2, STAT3,Bax and caspase-3 as well as increased protein expression of P-JAK2, P-STAT3 and activated caspase-3 (c-caspase-3). Moreover, the MDA levels were up-regulated in the NC and model groups. In contrast, opposing trends were found in the AG490 group compared with the NC and model groups. Conclusion: These data demonstrate that inhibiting the SOCS1-JAK2-STAT3 signaling pathway can reduce the loss of nerve function and apoptosis of neuronal cells, which provides a new target for the clinical treatment of ischemic stroke.

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“…S. aureus suppresses the T-cell IL-2 response to alloantigen via downregulation of HLA-DR and CD86 in an IL-10 dependent manner and increases the expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1). Those mechanisms suggest that T-cell IL-2 is affected by S. aureus through modulation of monocyte/macrophage antigen-presenting cell function [88, 89]. …”

Section: Adaptive Immunitymentioning

confidence: 99%

<b><i>Staphylococcus aureus</i></b> and Host Immunity in Recurrent Furunculosis

Nowicka

Grywalska

2019

Dermatology

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Staphylococcus aureus is one of the severest and most persistent bacterial pathogens. The most frequent S. aureus infections include impetigo, folliculitis, furuncles, furunculosis, abscesses, hidradenitis suppurativa, and mastitis. S. aureus produces a great variety of cellular and extracellular factors responsible for its invasiveness and ability to cause pathological lesions. Their expression depends on the growth phase, environmental factors, and location of the infection. Susceptibility to staphylococcal infections is rooted in multiple mechanisms of host immune responses and reactions to bacterial colonization. Immunological and inflammatory processes of chronic furunculosis are based on the pathogenicity of S. aureus as well as innate and acquired immunity. In-depth knowledge about them may help to discover the whole pathomechanism of the disease and to develop effective therapeutic options. In this review, we focus on the S. aureus-host immune interactions in the pathogenesis of recurrent furunculosis according to the most recent experimental and clinical findings.

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Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins

Cited by 59 publications

References 218 publications

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

<b><i>Staphylococcus aureus</i></b> and Host Immunity in Recurrent Furunculosis

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