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Introduction Cellular metabolism drives [CD4.sup.+] T cell differentiation and stability, and [CD4.sup.+] T cell metabolic pathways are promising therapeutic targets for cancers, autoimmune diseases, and asthma (1-3). Once activated, effector [...], Female individuals have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared with female individuals, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined that females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and that AR signaling attenuated glutamine uptake in [CD4.sup.+] T cells by reducing expression of glutamine transporters. In patients with asthma, circulating Th17 cells from men had minimal reliance upon glutamine uptake compared to Th17 cells from women. AR signaling thus attenuates glutaminolysis, demonstrating sexspecific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.

Background: Anti‐inflammatory effects of incretin signaling through the glucagon‐like peptide‐1 receptor (GLP‐1R) and the glucose‐dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP‐1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP‐1R and GIPR signaling together additively inhibits allergen‐induced lung and airway inflammation. Methods: WT (C57BL/6J), GLP‐1R knockout (KO), GIPR KO, and GLP‐1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt‐Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen‐induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). Results: Alt‐Ext‐induced IL‐33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP‐1R/GIPR DKO mice challenged with Alt‐Ext compared to the other strains. Furthermore, Alt‐Ext‐induced protein expression of IL‐5, IL‐13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP‐1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM‐1 expression on lung epithelial cells was increased in GLP‐1R/GIPR DKO mice challenged with Alt‐Ext compared to the other 3 strains. Conclusions: Deficiency of both GLP‐1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP‐1R and GIPR signaling should be explored for the treatment of asthma. [ABSTRACT FROM AUTHOR]

Introduction A sex bias exists in many autoimmune diseases and chronic inflammatory disorders, including asthma. Before puberty, males have increased asthma prevalence compared with females. After puberty, females have increased [...], Women have higher prevalence of asthma compared with men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. [Foxp3.sup.+] Tregs suppress and [ST2.sup.+] Tregs promote allergic airway inflammation. Clinical studies showed that the androgen dehydroepiandrosterone (DHEA) reduced asthma symptoms in patients, and mouse studies showed that androgen receptor (AR) signaling decreased allergic airway inflammation. Yet the impact of AR signaling on lung Tregs remains unclear. Using AR-deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext; allergen) challenge by stabilizing [Foxp3.sup.+] Tregs and limiting the number of [ST2.sup.+] ex-Tregs and IL-[13.sup.+] Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext-induced [ST2.sup.+] Tregs in mice by limiting expression of Gata2, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5[alpha]-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext-induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.

Introduction Tregs are important components of the adaptive immune system that promote tolerance, prevent the development of autoimmune diseases, and suppress inflammation (1, 2). Tregs are characterized by their expression [...], Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I2 ([PGI.sub.2]) promoted immune tolerance in models of allergic inflammation; however, the effect of [PGI.sub.2] on Treg function was not investigated. Tregs from mice deficient in the [PGI.sub.2] receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which [PGI.sub.2] signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg's ability to suppress Th2 responses. Using fate-mapping mice, we reported that [PGI.sub.2] signaling prevents Treg reprogramming toward a pathogenic phenotype. [PGI.sub.2] analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of [beta]-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that [PGI.sub.2] signaling licenses Treg suppressive function and that [PGI.sub.2] is a therapeutic target for enhancing Treg function.

Introduction Although the traditional view has been that cigarette smoking causes chronic obstructive pulmonary disease (COPD) through accelerated age-related lung-function decline in susceptible smokers, over the last several years it [...], Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-[kappa]B activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage (P3-P5) but not alveolar stage (P10-P12) of lung development disrupted elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progressed through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation downregulated elastin and fibulin-5 expression by saccular-stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. Although neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early-life predisposition to COPD.

Dual GIPR and GLP-1R agonist tirzepatide inhibits aeroallergen-induced allergic airway inflammation in mouse model of obese asthma At first, we hypothesized that GLP-1R and GIPR dual agonist treatment is more effective in reducing aeroallergen-induced allergic lung inflammation compared with either selective GLP-1R or GIPR agonist treatment. The Alt-Ext-induced eosinophils were significantly decreased in semaglutide and tirzepatide treatment groups compared with vehicle treatment group (Figure 2K), and all drug treatments significantly decreased the number of lymphocytes compared with vehicle treatment (Figure 2L). Further, tirzepatide treatment significantly decreased the number of Th2 in the lung, but neither [D-Ala SP 2 sp ]-GIP nor semaglutide treatment showed a decrease of Th2 compared with vehicle treatment. [Extracted from the article]

The article focuses on the potential therapeutic effects of prostaglandin I2 (PGI2) in patients with pulmonary arterial hypertension (PAH). Topics include the role of inflammation and immune responses in PAH, the vasoprotective effects of PGI2, and the hypothesis that PGI2 therapy can increase regulatory T cell (Treg) percentages and decrease the T effector cell (Teff) to Treg ratio in PAH patients.

Rhinovirus (RV) infections trigger exacerbations of airways disease, but underlying mechanisms remain unknown. We hypothesized that RV and cytokines present in inflamed airways combine to induce augmented airway epithelial cell chemokine expression, promoting further inflammation. To test this hypothesis in a cellular system, we examined the combined effects of RV39 and TNF-[alpha], a cytokine increased in asthma and chronic obstructive pulmonary disease, on airway epithelial cell pro-inflammatory gene expression. Costimulation of 16HBE14o--human bronchial epithelial cells and primary mucociliary-differentiated tracheal epithelial cells with RV and TNF-[alpha] induced synergistic increases in IL-8 and epithelial neutrophil attractant-78 production. Similar synergism was observed for IL-8 promoter activity, demonstrating that the effect is transcriptionally mediated. Whereas increases in ICAM-1 expression and viral load were noted 16-24 h after costimulation, cooperative effects between RV39 and TNF-[alpha] were evident 4 h after stimulation and maintained despite incubation with blocking antibody to ICAM-1 given 2 h postinfection or UV irradiation of virus, implying that effects were not solely due to changes in ICAM-1 expression. Furthermore, RV39 infection induced phosphorylation of ERK and transactivation of the IL-8 promoter AP-1 site, which functions as a basal level enhancer, leading to enhanced TNF-[alpha] responses. We conclude that RV infection and TNF-[alpha] stimulation induce cooperative increases in epithelial cell chemokine expression, providing a cellular mechanism for RV-induced exacerbations of airways disease. asthma; ERK; chronic obstructive pulmonary disease; intercellular adhesion molecule-1 ; interleukin-8