Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus

Is, Leikfoss; Il, Mero; Dahle, Maria K.; Ba, Lie; Hf, Harbo; Spurkland, Anne; Berge, Tone

doi:10.1038/gene.2012.52

Cited by 34 publications

(48 citation statements)

References 35 publications

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“…Aside from the tight LD observed in the associated locus, the pursuit of revealing the diseasecausing variant has been hindered by the lack of association of nsSNPs [1,8,12] and inconclusive evidence that the associated intronic SNPs exert transcriptional effects on CLEC16A and its surrounding genes [1,[13][14][15] and Marchand et al 2009 and Zouk et al 2102 (unpublished results). Therefore, before uncovering such potential causal variants, it is imperative that we gain more insight into the largely unknown function of the CLEC16A protein to decipher how these variants, when discovered, would affect protein function and consequent disease pathology.…”

Section: Discussionmentioning

confidence: 99%

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

Zouk

d’Hennezel

et al. 2014

Clinical and Experimental Immunology

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SummaryThe type 1 diabetes-associated 16p13 locus contains the CLEC16A gene. Its preferential immune cell expression suggests involvement in autoimmunity. Given its elevated expression in dendritic and B cells -known professional antigen-presenting cells (APCs) -we hypothesize that C-type lectin domain family 16 member A (CLEC16A) may be involved in T cell co-stimulation and consequent activation and proliferation. We also sought to identify CLEC16A's subcellular localization. The effect of the CLEC16A knock-down (KD) on B cell co-stimulation and activation of T cells was tested in human lymphoblastoid cell lines (LCLs) by co-culture with CD4 + T cells. T cell activation and proliferation were determined by flow-cytometric analysis of CD69 and CD25 expression and carboxyfluorescein succinimidyl ester (CFSE) dilution, respectively. CLEC16A subcellular localization in K562 cells was examined by immunofluorescence. We show that the CLEC16A KD did not affect the tested indices of lymphoblastoid cell line (LCL) APC capacity. Additionally, the percentage of activated T cells following LCL co-culture was not affected significantly by the CLEC16A KD. T cells co-cultured with KD or control LCLs also exhibited similar cell division profiles. CLEC16A co-localized with an endoplasmic reticulum (ER) marker, suggesting that it may be an ER protein. In conclusion, CLEC16A may not be involved in T cell co-stimulation. Additional studies on CLEC16A, accounting for its ER localization, are needed to uncover its biological role.

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Section: Discussionmentioning

confidence: 99%

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

Zouk

d’Hennezel

et al. 2014

Clinical and Experimental Immunology

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“…Dysregulation of SOCS expression has been implicated in several inflammatory diseases, including models of multiple sclerosis (65)(66)(67)(68)(69), rheumatoid arthritis (70,71), systemic lupus erythematosus (72,73), psoriasis (74,75), type 1 diabetes (51, 76 -79), sepsis (80,81), and also in human allergic disease (82)(83)(84). Furthermore, deficiencies in SOCS1 expression have been observed in the smooth muscle in airways (85), and epithelial cells (86) of asthmatic patients and functional SOCS1 polymorphism have been correlated with the development of adult onset asthma and increased IgE levels (87,88).…”

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

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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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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“…Although the role of heredity is yet to be fully understood, variations in specific genes, especially those relating to inflammation, have been associated with an increased risk of MS and corresponds well with the increased inflammatory response observed in the advancement of MS. [6][7][8][9] This is further supported by the increased incidence of MS in those with dysregulation of T-cell differentiation, particularly effector T cells. 7,9 Naïve CD4 + T cells can mature into different effector T-cell types including helper T (T H ) (T H 1, T H 2, and T H 17) and regulatory T (Treg) cells. 10 IFN-γ-secreting T H 1 cells and interleukin (IL) 17-secreting T H 17 cells are present in MS lesions in the CNS and are known to be integral in the pathogenesis of MS in human and mouse models.…”

Section: Multiple Sclerosis (Ms) Is a Neurodegenerative Disease Charamentioning

confidence: 55%

“…28,152 When cytokine function is abnormal, this leads to an autoimmune reaction within the body. Thus, cytokine regulation is a good potential therapeutic target for patients with MS. 9 The upregulation of IL-23 is widely accepted as a key checkpoint in the pathogenesis of MS because of its protective and differentiative role in T H 17 cells. 7 Finding ways to decrease the elevated serum and CNS levels of IL-23 in MS and EAE models is a major point of interest.…”

Section: Discussionmentioning

confidence: 99%

“…149,150 Polymorphisms of this MS risk allele (especially a SNP at rs12708716 found within intron 19 of CLEC16A that results in reduced SOCS1 expression) influence the susceptibility for various autoimmune diseases, specifically MS, through the reduction in SOCS1 protein expression in the thymus. 9 It has been reported that in the absence of the SOCS1 protein, mice experienced systemic inflammation as well as the development of thymocytes. 148 These symptoms are similar to those observed in MS, providing further evidence that the SOCS1 gene plays an important role in the pathogenesis of MS, with reduction in SOCS1 expressions leaving DCs over-responsive to cytokines and resulting in autoimmunity as discussed above.…”

Section: Suppressor Of Cytokine Signaling and Its Association With Msmentioning

confidence: 99%

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Involvement of Immune Regulation in Multiple Sclerosis

Spagnuolo

Piavis

Williams

2017

Immunol Immunogenet Insights

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Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuroinflammation and demyelination that results in axon loss. Multiple sclerosis has been shown to be the result of an autoimmune response caused by a mixture of genetic and environmental factors. Dendritic cells are prominent antigen-presenting cells that interact with various molecules to regulate the immune system. The dysfunction of various features of immune regulation, including interleukins (ILs), CD4 + T cells, and suppressor of cytokine signaling (SOCS1), has been implicated in the pathogenesis of MS. T cells, particularly through the malfunction of B7-costimulatory pathways, have been shown to affect the progression of the disease. SOCS1 is important in regulating the function of T cells through its interactions with other nearby genes, especially CLEC16A, with abnormal decreases in SOCS1 expression leading to the exhibition of MS symptoms. The activation of IL-23 receptors on CD4 + T cells is pivotal to their differentiation into pathogenic T H 17 cells. Several promising compounds that downregulate gene expression of IL-23 and IL-23R have been discovered but require further investigation for efficacy and safety. Given their role in the severity and progression of MS, therapies that decrease these dysregulations may ultimately decrease symptoms and in turn improve patients' quality of life.

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Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus

Cited by 34 publications

References 35 publications

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

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

Involvement of Immune Regulation in Multiple Sclerosis

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