Mice Expressing Cosegregating Single Nucleotide Polymorphisms (D298G and N397I) in TLR4 Have Enhanced Responses to House Dust Mite Allergen

Fink, Marc Y.; Qi, Xiulan; Shirey, Kari Ann; Fanaroff, Rachel; Chapoval, Svetlana P; Viscardi, Rose M.; Vogel, Stefanie N.; Keegan, Achsah

doi:10.4049/jimmunol.2100926

Cited by 4 publications

(4 citation statements)

References 63 publications

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“…The toll-like receptor (TLR) is one of the most studied pathogen detection systems and plays a central role in host defense [49]. In a type 2 immune response, IL-33 binds to the receptors ST2 and IL-1RAcP to form a heterodimer.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Renifolin F on Airway Allergy in an Ovalbumin-Induced Asthma Mouse Model In Vivo

Zhi-hong

et al. 2022

Molecules

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Renifolin F is a prenylated chalcone isolated from Shuteria involucrata, a traditional minority ethnic medicine used to treat the respiratory diseases and asthma. Based on the effects of the original medicine plant, we established an in vivo mouse model of allergic asthma using ovalbumin (OVA) as an inducer to evaluate the therapeutic effects of Renifolin F. In the research, mice were sensitized and challenged with OVA to establish an allergic asthma model to evaluate the effects of Renifolin F on allergic asthma. The airway hyper-reactivity (AHR) to methacholine, cytokine levels, ILC2s quantity and mircoRNA-155 expression were assessed. We discovered that Renifolin F attenuated AHR and airway inflammation in the OVA-induced asthmatic mouse model by inhibiting the regulation of ILC2s in the lung, thereby, reducing the upstream inflammatory cytokines IL-25, IL-33 and TSLP; the downstream inflammatory cytokines IL-4, IL-5, IL-9 and IL-13 of ILC2s; and the co-stimulatory factors IL-2 and IL-7; as well as the expression of microRNA-155 in the lung. The findings suggest a therapeutic potential of Renifolin F on OVA-induced airway inflammation.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Renifolin F on Airway Allergy in an Ovalbumin-Induced Asthma Mouse Model In Vivo

Zhi-hong

et al. 2022

Molecules

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“…WT and Plexin B1 KO mice were treated with HDM allergenic extract (lot no. 360924, Greer Laboratories, endotoxin concentration: 13.14 EU/50 μg HDM dose) as previously described ( 27 ). Briefly, 50 μg of extract in 5̃ μl PBS was applied to anesthetized mice intranasally four times six days apart.…”

Section: Methodsmentioning

confidence: 99%

“…Lungs were obtained from euthanized WT and Plexin B1 KO mice after completion of the allergen treatment protocols and prepared as previously described ( 27 , 30 ). N = 3-7 mice per experimental group in 3-4 independent experiments were used.…”

Section: Methodsmentioning

confidence: 99%

“…Lung sections were evaluated by an investigator blinded to the experimental conditions. H&E and PAS stains were evaluated as previously described ( 27 , 30 ): for H&E, 0, no signs of inflammation; 1, light and dispersed infiltrate in only a few areas of the section; 2, modest infiltrate surrounding major vessels and airways, with little in distal airway unit; 3, moderate infiltrate surrounding <50% of distal airways and vessels; and 4, heavy and focused eosinophilic infiltrate surrounding numerous distal vessels and airways, signs of increased alveolar macrophage numbers with macrophage fusions and extracellular matrix deposition. For PAS: 0, no signs of mucus in airways or elevated numbers of PAS+ cells; 1, no mucus in airways, slight increase in numbers of PAS+ cells in a few major airways; 2, some mucus detectable in major airways; 3, mucus detected in major airways with <50% of distal airway epithelial cells PAS+ in distal airway units; and 4, mucus plugging of airways observed in several airways and majority of distal airway epithelial cells are PAS+ in multiple distal airways per section.…”

Section: Methodsmentioning

confidence: 99%

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Plexin B1 controls Treg numbers, limits allergic airway inflammation, and regulates mucins

Chapoval,

Gao,

Fanaroff

et al. 2024

Front. Immunol.

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We investigated the effect of global Plexin B1 deficiency on allergic airway responses to house dust mite (HDM) or ovalbumin (OVA). In the HDM model, there were higher Th2 cytokine levels in the BALF of Plexin B1 knock-out (KO) mice compared to wild type (WT), and tissue inflammation and mucus production were modestly enhanced. In the OVA model, Plexin B1 deficiency led to increases in lung inflammation, mucus production, and lung Th2 cytokines accompanied by dysregulated mucin gene expression without affecting anti-OVA IgE/IgG1 levels. Spleen cells from Plexin B1 KO mice proliferated more robustly than WT cells in vitro to a variety of stimuli. Plexin B1 KO CD4+ T cells from spleens expressed higher levels of Ki-67 and CD69 compared to WT cells. Spleen cells from naïve Plexin B1 KO mice secreted increased amounts of IL-4 and IL-6 when pulsed in vitro with OVA whereas in vivo OVA-primed spleen cells produced IL-4/IL-5 when subjected to in vitro OVA restimulation. The upregulated allergic inflammatory response in Plexin B1 KO mice was associated with a lower number of Tregs in the lung tissues. Moreover, these mice displayed lower numbers of Treg cells in the lymphoid tissues at the baseline. These results demonstrate a previously unrecognized link between Plexin B1, Treg cells, and mucus in allergic lung inflammation.

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M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice

Vlk,

Prantner,

Shirey

et al. 2023

mBio

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Toll-like receptor 4 (TLR4) is an innate immune receptor responsive to lipopolysaccharide (LPS). Single nucleotide polymorphisms (SNPs) in human TLR4 that encode an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I) render individuals hyporesponsive to LPS. In humans, these SNPs are also associated with increased susceptibility to inflammatory bowel diseases (IBDs). Using knock-in mice engineered to express the murine homologs of these human TLR4 mutations (“TLR4-SNP” mice), we have shown that TLR4-SNP mice develop significantly more severe colitis induced by dextran sodium sulfate (DSS) than wild-type (WT) mice, similar to IBD in humans expressing these SNPs. Previous studies have provided indirect evidence for “tissue repair” M2 macrophages (Mφ) in the resolution of colitis. Signaling through the IL-4/IL-13 receptor, IL-4Rα, and the transcription factor, peroxisome proliferator-activated receptor (PPARγ), have been shown to be required for induction of M2a Mφ, and our data provide direct evidence for the involvement of both in the repair of DSS-induced colonic damage. In response to DSS, colons of TLR4-SNP mice produced reduced levels of M2a Mφ marker mRNA and protein, including PPARγ, and therapeutic administration of the PPARγ agonist ligand, rosiglitazone, resolved colitis in TLR4-SNP mice, and increased expression of the M2a protein, Ym1. Together, these data indicate that the failure of TLR4-SNP mice to resolve DSS-induced colitis may be secondary to their failure to induce “tissue repair” M2a Mφ. IMPORTANCE Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, impacts millions of individuals worldwide and severely impairs the quality of life for patients. Dysregulation of innate immune signaling pathways reduces barrier function and exacerbates disease progression. Macrophage (Mφ) signaling pathways are potential targets for IBD therapies. While multiple treatments are available for IBD, (i) not all patients respond, (ii) responses may diminish over time, and (iii) treatments often have undesirable side effects. Genetic studies have shown that the inheritance of two co-segregating SNPs expressed in the innate immune receptor, TLR4, is associated with human IBD. Mice expressing homologous SNPs (“TLR4-SNP” mice) exhibited more severe colitis than WT mice in a DSS-induced colonic inflammation/repair model. We identified a critical role for M2a “tissue repair” Mφ in the resolution of colitis. Our findings provide insight into potential development of novel therapies targeting Mφ signaling pathways that aim to alleviate the debilitating symptoms experienced by individuals with IBD.

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Mice Expressing Cosegregating Single Nucleotide Polymorphisms (D298G and N397I) in TLR4 Have Enhanced Responses to House Dust Mite Allergen

Cited by 4 publications

References 63 publications

Therapeutic Effect of Renifolin F on Airway Allergy in an Ovalbumin-Induced Asthma Mouse Model In Vivo

Therapeutic Effect of Renifolin F on Airway Allergy in an Ovalbumin-Induced Asthma Mouse Model In Vivo

Plexin B1 controls Treg numbers, limits allergic airway inflammation, and regulates mucins

M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice

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