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1.
Nat Commun ; 13(1): 4435, 2022 07 30.
Article in English | MEDLINE | ID: mdl-35908044

ABSTRACT

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.


Subject(s)
Asthma , Pneumonia , Allergens , Animals , Asthma/metabolism , Cytokines/metabolism , Immunity, Innate , Inflammation/metabolism , Interleukin-33/genetics , Interleukin-33/metabolism , Lung/metabolism , Lymphocytes/metabolism , Mice , Pneumonia/genetics , Pneumonia/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Receptors, Leukotriene
2.
Front Immunol ; 12: 618807, 2021.
Article in English | MEDLINE | ID: mdl-33679760

ABSTRACT

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.


Subject(s)
Alternaria/immunology , Alternariosis/immunology , Cyclic GMP/analogs & derivatives , Immunity, Innate , Lung/immunology , Membrane Proteins/immunology , Pneumonia/immunology , Alternariosis/genetics , Alternariosis/pathology , Animals , Cyclic GMP/genetics , Cyclic GMP/immunology , Cytokines/genetics , Cytokines/immunology , Inflammation/genetics , Inflammation/immunology , Inflammation/microbiology , Inflammation/pathology , Lung/microbiology , Lung/pathology , Membrane Proteins/genetics , Mice , Mice, Knockout , Pneumonia/genetics , Pneumonia/microbiology , Pneumonia/pathology , Signal Transduction/genetics , Signal Transduction/immunology
3.
Invest Ophthalmol Vis Sci ; 61(6): 2, 2020 06 03.
Article in English | MEDLINE | ID: mdl-32492110

ABSTRACT

Purpose: Epithelial to mesenchymal transition (EMT) is a cause of anterior and posterior subcapsular cataracts. Central to EMT is the formation of actin stress fibers. Selective targeting of actin stress fiber-associated tropomyosin (Tpm) in epithelial cells may be a means to prevent stress fiber formation and repress lens EMT. Methods: We identified Tpm isoforms in mouse immortalized lens epithelial cells and epithelial and fiber cells from whole lenses by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) followed Sanger sequencing. We focused on the role of one particular tropomyosin isoform, Tpm3.1, in EMT. To induce EMT, we treated cells or native lenses with TGFß2. To test the function of Tpm3.1, we exposed cells or whole lenses to a Tpm3.1-specific chemical inhibitor, TR100, as well as investigated lenses from Tpm3.1 knockout mice. We examined stress fiber formation by confocal microscopy and assessed EMT progression by analysis of alpha-smooth muscle actin (αSMA) mRNA (real-time RT-PCR), and protein (Western immunoassay [WES]). Results: Lens epithelial cells express eight Tpm isoforms. Cell culture studies showed that TGFß2 treatment results in the upregulation of Tpm3.1, which associates with actin in stress fibers. TR100 prevents stress fiber formation and reduces αSMA in TGFß2-treated cells. Using an ex vivo lens culture model, TGFß2 treatment results in stress fiber formation at the basal regions of the epithelial cells. Genetic knockout of Tpm3.1 or treatment of lenses with TR100 prevents basal stress fiber formation and reduces epithelial αSMA levels. Conclusions: Targeting specific stress fiber associated tropomyosin isoform, Tpm3.1, is a means to repress lens EMT.


Subject(s)
Actins/genetics , Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition/physiology , Lens, Crystalline/cytology , Stress Fibers/metabolism , Tropomyosin/metabolism , Animals , Blotting, Western , Cell Survival , Epithelial Cells/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Protein Isoforms/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta2/pharmacology
5.
J Cell Sci ; 131(23)2018 11 29.
Article in English | MEDLINE | ID: mdl-30333143

ABSTRACT

Tropomyosins (Tpms) stabilize F-actin and regulate interactions with other actin-binding proteins. The eye lens changes shape in order to focus light to transmit a clear image, and thus lens organ function is tied to its biomechanical properties, presenting an opportunity to study Tpm functions in tissue mechanics. Mouse lenses contain Tpm3.5 (also known as TM5NM5), a previously unstudied isoform encoded by Tpm3, which is associated with F-actin on lens fiber cell membranes. Decreased levels of Tpm3.5 lead to softer and less mechanically resilient lenses that are unable to resume their original shape after compression. While cell organization and morphology appear unaffected, Tmod1 dissociates from the membrane in Tpm3.5-deficient lens fiber cells resulting in reorganization of the spectrin-F-actin and α-actinin-F-actin networks at the membrane. These rearranged F-actin networks appear to be less able to support mechanical load and resilience, leading to an overall change in tissue mechanical properties. This is the first in vivo evidence that a Tpm protein is essential for cell biomechanical stability in a load-bearing non-muscle tissue, and indicates that Tpm3.5 protects mechanically stable, load-bearing F-actin in vivoThis article has an associated First Person interview with the first author of the paper.


Subject(s)
Actins/metabolism , Lens, Crystalline/metabolism , Tropomyosin/metabolism , Animals , Cell Differentiation , Mice
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