Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung

Zimmer, Jana; Weitnauer, Michael; Boutin, Sébastien; Küblbeck, Günter; Thiele, Sabrina; Walker, Patrick; Lasitschka, Felix; Lunding, Lars; Orinska, Zane; Vock, Christina; Arnold, Bernd; Wegmann, Michael; Dalpke, Alexander H.

doi:10.3389/fimmu.2016.00514

Cited by 14 publications

(7 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In patients with severe asthma, decreased SOCS1 expression correlated with eosinophilia and Th2-driven inflammation ( 28 ). Furthermore, mice with a selective knockout of the nuclear localization sequence (NLS) of SOCS1 presented with low-grade pulmonary inflammation and an increase in Th2-type cytokines ( 13 ). In our patients Th2-type cytokines in CD4+ T cells were not elevated as compared to healthy controls, emphasizing the importance of local effects such as inflammation of SOCS1 in different tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from this particular function of SOCS1, other investigations suppose that SOCS1 impacts on multiple immune pathways beyond enhanced signal transducer and activator of transcription (STAT) 1 phosphorylation ( 13 – 15 ) ( Figure 1A ) . SOCS1 additionally functions as an E3 ligase substrate ( 16 ): SOCS1 binds to ElonginB/C via interaction of the C-terminal SOCS-box domain, to form a Cullin5 Rbx2 E3 ligase complex ( 12 ) ( Figure 1B ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency

et al. 2021

View full text Add to dashboard Cite

BackgroundInborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans.ObjectiveWe sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency.MethodsWe assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells.ResultsSOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients.ConclusionsSOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency

et al. 2021

View full text Add to dashboard Cite

show abstract

“…SOCS1 is known to regulate Th2‐cytokine signaling in both in‐vitro cell cultures and in‐vivo mouse models. It blocks the phosphorylation of STAT6 through inhibiting JAK activity, and has been identified as a negative feedback regulator of the JAK/STAT6 pathway . Mucosal SOCS1 is increased in patients with AR and asthma compared with healthy controls .…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐17A potentiates interleukin‐13‒induced eotaxin‐3 production by human nasal epithelial cells from patients with allergic rhinitis

Wang

Zhu

et al. 2019

Int Forum Allergy Rhinol

View full text Add to dashboard Cite

Background: Interleukin (IL)-17A is involved in the pathogenesis of allergic rhinitis (AR). Increased expression of IL-17A is correlated with disease severity and nasal eosinophilia. However, the molecular mechanisms by which IL-17A contributes to T-helper 2 cytokine IL-13-driven pathology in AR remain unclear. We sought to obtain mechanistic insight into how IL-17A and IL-13 regulate the epithelial production of eotaxin-3 representing eosinophilic inflammation in AR. Methods:Human nasal epithelial cells (HNECs) from AR patients were cultured and stimulated with IL-17A, IL-13, or IL-17A and IL-13. Phosphorylated signal transducer activator of transcription 6 (p-STAT6) and suppressor of cytokine signaling 1 (SOCS1) in HNECs were assayed using Western blo ing. Immunocytochemistry was used to determine p-STAT6-positive expression in the cells. Eotaxin-3 expression in the cells and culture supernatants was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assays. Results:Stimulation with IL-13 alone induced STAT6 phosphorylation and promoted p-STAT6 nuclear translocation, leading to eotaxin-3 production by HNECs. These effects were further enhanced by cotreatment with IL-13 and IL-17A, whereas IL-17A alone had no impact on STAT6 or eotaxin-3 expression. Incubation with IL-17A or IL-13 increased the level of SOCS1 protein in the cells, whereas the addition of IL-17A a enuated IL-13-induced SOCS1 expression.Conclusion: IL-17A potentiated IL-13-driven STAT6 activation through the downregulation of SOCS1 expression, leading to enhancement of eotaxin-3 production by HNECs. These factors contributed to eosinophilic inflammation in AR. C 2019 ARS-AAOA, LLC. Key Words:allergic rhinitis; interleukin-17A; interleukin-13; eotaxin-3; signal transducer activator of transcription 6; suppressor of cytokine signaling 1 How to Cite this Article: Wang WW, Zhu K, Yu HW, Pan YL. Interleukin-17A potentiates interleukin-13-induced eotaxin-3 production by human nasal epithelial cells from patients with allergic rhinitis. Int Forum Allergy Rhinol. 2019;9:1327-1333.A llergic rhinitis (AR) is a chronic inflammatory disease with a prevalence of 10%-40%. 1 CD4 + T-helper (Th) cells play a vital role in local mucosal immune responses of allergic airway diseases. 2 AR has long been hypothesized as the result of dysregulation of the balance between Th1 and

show abstract

“…Zimmer et al adopted an elegant tool to study the nucleus-located SOCS1 by replacing its NLS. They found that mice lacking nuclear SOCS1, but not cytoplasmic SOCS1, do not have neonatal lethal symptoms, but have mild airway inflammation, indicating different roles of nucleus located and cytoplasm located SOCS1 (65).…”

Section: Socs1 Deficiencymentioning

confidence: 99%

Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity

et al. 2021

View full text Add to dashboard Cite

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

show abstract

Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung

Cited by 14 publications

References 77 publications

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency

Interleukin‐17A potentiates interleukin‐13‒induced eotaxin‐3 production by human nasal epithelial cells from patients with allergic rhinitis

Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity

Contact Info

Product

Resources

About