Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes.
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ABSTRACT:
SUBMITTER: Lee S
PROVIDER: S-EPMC8410019 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMany studies have found that smoking reduces lung function, but the relationship between cigarette smoke and allergic asthma has not been clearly elucidated, particularly the role of mast cells. This study aimed to investigate the effects of smoke exposure on allergic asthma and its association with mast cells.MethodsBALB/c mice were sensitized and challenged by OVA to induce asthma, and bone marrow-derived mast cells (BMMCs) were stimulated with antigen/antibody reaction. Mice or BMMCs were exposed to cigarette smoke or CSE solution for 1 mo or 6 h, respectively. The recruitment of inflammatory cells into BAL fluid or lung tissues was determined by Diff-Quik or H&E staining, collagen deposition by Sircol assay, penh values by a whole-body plethysmography, co-localization of tryptase and Smad3 by immunohistochemistry, IgE and TGF-β level by ELISA, expressions of Smads proteins, activities of signaling molecules, or TGF-β mRNA by immunoblotting and RT-PCR.ResultsCigarette smoke enhanced OVA-specific IgE levels, penh values, recruitment of inflammatory cells including mast cells, expressions of smad family, TGF-β mRNA and proteins, and cytokines, phosphorylations of Smad2 and 3, and MAP kinases, co-localization of tryptase and Smad3, and collagen deposition more than those of BAL cells and lung tissues of OVA-induced allergic mice. CSE solution pretreatment enhanced expressions of TGF-β, Smad3, activities of MAP kinases, NF-κB/AP-1 or PAI-1 more than those of activated-BMMCs.ConclusionsThe data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-β/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling.
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Project description:The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1?. The NLRP3 inflammasome was reported to be essential for IL 1? release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1? at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.
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Project description:The inflammasome is a multi-protein platform that assembles upon the presence of cues derived from infection or tissue damage, and triggers the inflammatory response. Inflammasome components include sensor proteins that detect danger signals, procaspase 1 and the adapter ASC (apoptosis-associated speck-like protein containing a CARD) tethering these molecules together. Upon inflammasome assembly, procaspase 1 self-activates and renders functional cytokines to arbitrate in the defense mechanism. This assembly is mediated by self-association and protein interactions via Death Domains. The inflammasome plays a critical role in innate immunity and its dysregulation is the culprit of many autoimmune disorders. An in-depth understanding of the factors involved in inflammasome assembly could help fight these conditions. This review describes our current knowledge on the biophysical aspects of inflammasome formation from the perspective of ASC. The specific characteristics of the three-dimensional solution structure and interdomain dynamics of ASC are explained in relation to its function in inflammasome assembly. Additionally, the review elaborates on the identification of ASC interacting surfaces at the amino acid level using NMR techniques. Finally, the macrostructures formed by full-length ASC and its two Death Domains studied with Transmission Electron Microscopy are compared in the context of a directional model for inflammasome assembly.
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Project description:Allergic asthma is one of most famous allergic diseases, which develops lung and airway inflammation. Recent studies have revealed the relationship between the pathology of allergic asthma and the increase of host-derived DNA in inflamed lung, but the role of the DNA-recognizing innate immune receptor for the inflammation is unknown well. Here we investigated the role of Toll-Like Receptor 9 in the pathogenesis of allergic asthma without synthesized CpG-ODNs. To examine that, we analyzed the pathology and immunology of house-dust-mite (HDM)-induced allergic asthma in Tlr9-/- mice and TLR9-inhibitory-antibody-treated mice. In Tlr9-/- mice, airway hyperresponsiveness (AHR) and the number of eosinophils decreased, and production of the Th2 cytokines IL-13, IL-5, and IL-4 was suppressed, compared with in wild-type mice. Interestingly, unlike Th2 cytokine production, IL-17A production was increased in Tlr9-/- mice. Furthermore, production of IL-2, which decreases IL-17A production, was reduced in Tlr9-/- mice. Blockade of TLR9 by treatment with TLR9-inhibitory-antibody, NaR9, effectively suppressed the development of allergic asthma pathology. IL-17A production in NaR9-treated mice was enhanced, which is comparable to Tlr9-/- mice. These results suggest that the TLR9-IL-2 axis plays an important role in Th2 inflammation by modulating IL-17A production in HDM-induced allergic asthma and that targeting of TLR9 might be a novel therapeutic method for allergic asthma.
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Project description:Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:
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Project description:The small GTPase RhoA and its downstream effectors are critical regulators in the pathophysiological processes of asthma. The underlying mechanism, however, remains undetermined. Here, we generated an asthma mouse model with RhoA-conditional KO mice (Sftpc-cre;RhoAfl/fl) in type II alveolar epithelial cells (AT2) and demonstrated that AT2 cell-specific deletion of RhoA leads to exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, Sftpc-cre;RhoAfl/fl mice showed a significant reduction in Tgf-β1 levels in BALF and lung tissues, and administration of recombinant Tgf-β1 to the mice rescued Tgf-β1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoAfl/fl mice. Using RNA sequencing technology, we identified Slc26a4 (pendrin), a transmembrane anion exchange, as the most upregulated gene in RhoA-deficient AT2 cells. The upregulation of SLC26A4 was further confirmed in AT2 cells of asthmatic patients and mouse models and in human airway epithelial cells expressing dominant-negative RHOA (RHOA-N19). SLA26A4 was also elevated in serum from asthmatic patients and negatively associated with the percentage of forced expiratory volume in 1 second (FEV1%). Furthermore, SLC26A4 inhibition promoted epithelial TGF-β1 release and attenuated allergic airway inflammation. Our study reveals a RhoA/SLC26A4 axis in AT2 cells that functions as a protective mechanism against allergic airway inflammation.
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Project description:A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production.
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