The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy

Cardoso, Cássia Regina Primila; Provinciatto, Pauline R.; Godoi, Dannielle Fernandes; Fonseca, Monique T.; Ferreira, Beatriz Rossetti; Teixeira, Gerlinde Agate Platais Brasil; Cunha, Fernando; Pinzan, Camila Figueiredo; Silva, João

doi:10.1016/j.aller.2019.02.006

Cited by 8 publications

(11 citation statements)

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“…STAT6 is a signaling molecule that has been shown to differentially regulate IgG isotype classswitching in mice and humans. 14,[33][34][35][36][37][38][39][40][41][42][43][44][45]47,48 We therefore set out to test whether STAT6 signaling similarly regulated class-switching in response to both transfusion and vaccination.…”

Section: Results: Rbc Transfusion Induces a Different Igg Class Switc...mentioning

confidence: 99%

“…Given the observed differences in isotype class switching induced by transfusion vs. vaccination, we were interested in determining whether the molecular regulators of class switching might also be different between these immune stimuli. Since STAT6 is a wellknown regulator of IgG1 and IgG2 subtype class switching in multiple different vaccination and infectious settings 14,47,48,[33][34][35][36][37][38][39][40][41][42][43][44][45] , we created a novel STAT6 deficient mouse model to directly test whether STAT6 played a similar role in regulating isotype class-switching in response to transfusion. We used CRISPR/cas9 to target STAT6 in C57BL/6J embryos and confirmed successful disruption of STAT6 function.…”

Section: Discussionmentioning

confidence: 99%

“…STAT6 is a wellknown regulator of class switching, where, in mice it supports IgG1 and suppresses IgG2 subtypes. 14,[33][34][35][36][37][38][39][40][41][42][43][44][45] Thus, transfusion of STAT6 KO mice allows us to directly test whether the molecular mechanisms that regulate class-switching in response to RBC transfusion are similar or different from those that regulate class-switching in response to protein in Alum vaccination.…”

Section: Introductionmentioning

confidence: 99%

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Class switching is differentially regulated in RBC alloimmunization and vaccination

Prakash

Medved

Arneja

et al. 2023

Preprint

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BackgroundStudies of human patients have shown that most anti-RBC alloantibodies are IgG1 or IgG3 subclasses, though it is unclear why transfused RBCs preferentially drive these subclasses over others. Though mouse models allow for the mechanistic exploration of class-switching, previous studies of RBC alloimmunization in mice have focused more on the total IgG response than the relative distribution, abundance, or mechanism of IgG subclass generation. Given this major gap, we compared the IgG subclass distribution generated in response to transfused RBCs relative to protein in alum vaccination, and determined the role of STAT6 in their generation.Study Design and MethodsWT mice were either immunized with Alum/HEL-OVA or transfused with HOD RBCs and levels of anti-HEL IgG subtypes were measured using end-point dilution ELISAs. To study the role of STAT6 in IgG class-switching, we first generated and validated novel STAT6 KO mice using CRISPR/cas9 gene editing. STAT6 KO mice were then transfused with HOD RBCs or immunized with Alum/HEL-OVA, and IgG subclasses were quantified by ELISA.ResultsWhen compared to antibody responses to Alum/HEL-OVA, transfusion of HOD RBCs induced lower levels of IgG1, IgG2b and IgG2c but similar levels of IgG3. Class switching to most IgG subtypes remained largely unaffected in STAT6 deficient mice in response to HOD RBC transfusion, with the one exception being IgG2b. In contrast, STAT6 deficient mice showed altered levels of all IgG subtypes following Alum vaccination.DiscussionOur results show that anti-RBC class-switching occurs via alternate mechanisms when compared to the well-studied immunogen alum vaccination.

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Section: Results: Rbc Transfusion Induces a Different Igg Class Switc...mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Class switching is differentially regulated in RBC alloimmunization and vaccination

Prakash

Medved

Arneja

et al. 2023

Preprint

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“…To the best of our knowledge, these findings have demonstrated for the first time that TXL regulated the balance between Th17 and Treg cells and the associated inflammatory response. Provided that TXL exerted its roles in Alzheimer's disease by regulating JAK/STAT3 signaling pathway partly 17 and signal transducer and activator of transcription (STAT) proteins were crucial for regulating inflammation 28 and the function of Th17 and Treg cells, [29][30][31] we wonder how TXL affected JAK/STAT3 signaling pathway. The results affirmed that TXL treatment inhibited the activation of this pathway in a dose-dependent manner, suggesting that TXL played its protective role in lung capillary leak and lung injury at least partly by inhibiting JAK/STAT3 pathway.…”

Section: Discussionmentioning

confidence: 99%

Taxifolin ameliorates sepsis-induced lung capillary leak through inhibiting the JAK/STAT3 pathway

Shen

Lin²,

Qian

et al. 2022

aei

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Background: As a systemic inflammatory reaction, sepsis is associated with various organ dysfunctions. The capillary leakage and the imbalance between T helper 17 and regulatory T (Th17/Treg) cells are associated with sepsis-induced lung injury. Taxifolin (TXL) has been found to play a vital role in regulating this diverse disease. However, the detailed functioning and mechanism of TXL in regulating sepsis-induced lung capillary leak remain elusive. Methods: Balb/c mice were used to establish sepsis-induced lung injury model through administration of lipopolysaccharide (LPS). The structure of lung tissues was observed by using hematoxylin & eosin staining. Protein level and total cells in bronchoalveolar lavage fluid (BALF) were measured by bicinchoninic acid (BCA) protein assay kit and hematimetry assay, respectively. Quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were employed to detect the level of inflammatory cytokines. The content of Th17 and Treg cells were measured by flow cytometry analysis. Western blot assay was used to determine the protein level of retinoid-related orphan receptor-γt (RORγt), Forkhead box P3 (Foxp3), Janus kinase 2 (JAK2), phospho(p)-JAK2, signal transducer and activator of transcription 3 (STAT3), and phospho(p)-STAT3. Results: Taxifolin effectively prolonged the survival period of sepsis mice and alleviated LPS-induced lung injury in a dose-dependent manner. Moreover, TXL reduced LPS-induced increase in protein levels and T cell content in BALF, and effectively restored the wet:dry ratio of lung tissue and tissue permeability. Treating with TXL notably inhibited the production of pro-inflammatory cytokines induced by sepsis and influenced the balance between Th17 and Treg cells. Furthermore, TXL treatment suppressed the activation of JAK/STAT3 signaling pathway in a dose-dependent manner. Conclusion: Our findings revealed that TXL alleviated sepsis-induced capillary leak in the lungs of mice by regulating JAK/STAT3 signaling pathway.

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“…STAT6 is a signaling molecule that has been shown to differentially regulate IgG isotype class-switching in mice and humans. 14,[33][34][35][36][37][38][39][40][41][42][43][44][45]47,48 We therefore set out to test whether STAT6 signaling similarly regulated class-switching in response to both transfusion and vaccination.…”

Section: Rbc Transfusion Induces a Different Igg Class Switching Prof...mentioning

confidence: 99%

Class switching is differentially regulated in RBC alloimmunization and vaccination

et al. 2023

View full text Add to dashboard Cite

Background Studies of human patients have shown that most anti‐RBC alloantibodies are IgG1 or IgG3 subclasses, although it is unclear why transfused RBCs preferentially drive these subclasses over others. Though mouse models allow for the mechanistic exploration of class‐switching, previous studies of RBC alloimmunization in mice have focused more on the total IgG response than the relative distribution, abundance, or mechanism of IgG subclass generation. Given this major gap, we compared the IgG subclass distribution generated in response to transfused RBCs relative to protein in alum vaccination, and determined the role of STAT6 in their generation. Study Design and Methods WT mice were either immunized with Alum/HEL‐OVA or transfused with HOD RBCs and levels of anti‐HEL IgG subtypes were measured using end‐point dilution ELISAs. To study the role of STAT6 in IgG class‐switching, we first generated and validated novel STAT6 KO mice using CRISPR/cas9 gene editing. STAT6 KO mice were then transfused with HOD RBCs or immunized with Alum/HEL‐OVA, and IgG subclasses were quantified by ELISA. Results When compared with antibody responses to Alum/HEL‐OVA, transfusion of HOD RBCs induced lower levels of IgG1, IgG2b, and IgG2c but similar levels of IgG3. Class switching to most IgG subtypes remained largely unaffected in STAT6 deficient mice in response to HOD RBC transfusion, with the one exception being IgG2b. In contrast, STAT6 deficient mice showed altered levels of all IgG subtypes following Alum vaccination. Discussion Our results show that anti‐RBC class‐switching occurs via alternate mechanisms when compared with the well‐studied immunogen alum vaccination.

show abstract

The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy

Cited by 8 publications

References 38 publications

Class switching is differentially regulated in RBC alloimmunization and vaccination

Class switching is differentially regulated in RBC alloimmunization and vaccination

Taxifolin ameliorates sepsis-induced lung capillary leak through inhibiting the JAK/STAT3 pathway

Class switching is differentially regulated in RBC alloimmunization and vaccination

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