STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

Lee, Soojin; Shan, Jichuan; Aldossary, Haya; Gaudreault, Véronique; Bazett, Mark; Fixman, Elizabeth D.

doi:10.1002/eji.201847534

Cited by 10 publications

(3 citation statements)

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“…Data from several studies have shown that STAT6-IP reduces Th2-biased inflammatory responses in the lung (38, 59, 60). Our published and unpublished data provide support for STAT6-IP inhibition of responses in innate cells of the lung to control Th2 adaptive immunity (37, 38, 60). Our ongoing objectives are to clarify how STAT6-IP modulates the ability of IL-33 to interact with IL-13 and STAT6 to induce AAM differentiation and eosinophil activation.…”

Section: Discussionsupporting

confidence: 55%

“…To assess lung function, mice were anesthetized using xylazine and sodium pentobarbital and paralyzed with pancuronium bromide. Total lung elastance and resistance in response to increasing doses of methacholine was measured as previously described (37, 38). Briefly, anesthetized and paralyzed mice were attached to a computer-controlled small-animal ventilator (flexiVent; Scireq, Montréal, QC, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Sex Differences in IL-33-Induced STAT6-Dependent Type 2 Airway Inflammation

et al. 2019

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Sex differences in asthma prevalence are well-documented but poorly understood. Murine models have contributed to our understanding of mechanisms that could regulate this sex disparity, though the majority of these studies have examined responses present after Th2 adaptive immunity is established. We have now investigated how sex influences acute activation of innate cell populations in the lung upon initial exposure to the model antigen, ovalbumin (OVA), in the presence of IL-33 (OVA+IL-33), to prime the lungs for type 2 immunity. We also examined how inflammatory responses induced by OVA+IL-33 were altered in mice lacking the STAT6 transcription factor, which is activated by IL-13, an effector cytokine of IL-33. Our data demonstrate that type 2 inflammation induced by OVA+IL-33 was more severe in female mice compared to males. Females exhibited greater cytokine and chemokine production, eosinophil influx and activation, macrophage polarization to the alternatively activated phenotype, and expansion of group 2 innate lymphoid cells (ILC2s). While increases in ILC2s and eosinophils were largely independent of STAT6 in both males and females, many other responses were STAT6-dependent only in female mice. Our findings indicate that a subset of type 2 inflammatory responses induced by OVA+IL-33 require STAT6 in both males and females and that enhanced type 2 inflammation in females, compared to males, is associated with greater IL-13 protein production. Our findings suggest blunted IL-13 production in males may protect against type 2 inflammation initiated by OVA+IL-33 delivery to the lung.

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Section: Discussionsupporting

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Sex Differences in IL-33-Induced STAT6-Dependent Type 2 Airway Inflammation

et al. 2019

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“…The DCs expressing OX40L are an inducer of Th2 differentiation in asthma. 30 , 31 OX40L affects the regulation of DCs to Th2 cells differentiation in asthma. Hence, we thought that exploring the expression mechanism of OX40L in DCs is very meaningful for understanding the pathogenesis of asthma.…”

Section: Discussionmentioning

confidence: 99%

E3 Ubiquitin Ligase March1 Facilitates OX40L Expression in Allergen-Stimulated Dendritic Cells Through Mediating the Ubiquitination of HDAC11

Zhang¹,

Sun²,

Guo³

et al. 2021

JAA

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Background: It was demonstrated that membrane-associated RING-CH 1 (March 1) might play an important role in the pathogenesis of asthma. Methods: The levels of mRNA and protein were measured by qRT-PCR and Western blot, respectively. Immunofluorescence assay was used to determine whether March1 co-locates with HDAC11. Co-immunoprecipitation was performed to examine the combination of proteins. Moreover, luciferase assay was used to measure the promoter activity of genes. Results: The mRNA and protein levels of both March1 and OX40 ligand (OX40L) were increased in the dendritic cells (DCs) from asthmatic children and asthmatic animals. Histone deacetylase 11 (HDAC11) protein was decreased in the DCs from asthmatic children and asthmatic model. Increasing of March1 or decreasing of March1 only affect the expression of HDAC11 in protein level. Besides, increasing of HDAC11 could inhibit OX40L expression, and decreasing of HDAC11 promoted OX40L expression in house dust mites (HDMs)-treated DCs. Increasing of HDAC11 notably reversed the promotion of March1 to OX40L expression. Our data further proved that March1 reduced the protein level of HDAC11 through inducing ubiquitination and degradation. HDAC11 combined with krüppel-like factor 4 (KLF4) to decrease the activity of OX40L gene promoter, thus to downregulate the level of OX40L. Conclusion: Overall, our data showed that HDAC11 promoted KLF4-dependent OX40L decreasing. However, March1 promoted OX40L expression through enhancing the ubiquitination and degradation of HDAC11 and subsequent blocking the inhibition of HDAC11 to OX40L.

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