IL-23 signaling is not an important driver of liver inflammation and fibrosis in murine non-alcoholic steatohepatitis models.

Non-alcoholic fatty liver disease (NAFLD), represents an unmet medical need that can progress to non-alcoholic steatohepatitis (NASH), which, without intervention, can result in the development of cirrhosis and hepatocellular carcinoma (HCC). Inflammation is a pathological hallmark of NASH, and targeting key inflammatory mediators of NASH may lead to potential therapeutics for the disease. Herein, we aimed to investigate the role of IL-23 signaling in NASH progression in murine models. We showed that recombinant IL-23 can promote IL-17 producing cell expansion in the liver and that these cells are predominately γδ T cells and Mucosal Associated Invariant T cells (MAITs). Reciprocally, we found that IL-23 signaling is necessary for the expansion of γδ T cells and MAIT cells in the western diet (WD) diet induced NASH model. However, we did not observe any significant differences in liver inflammation and fibrosis between wild type and Il23r-/- mice in the same NASH model. Furthermore, we found that Il23r deletion does not impact liver inflammation and fibrosis in the choline-deficient, L-amino acid-defined and high-fat diet (CDA-HFD) induced NASH model. Based on these findings, we therefore propose that IL-23 signaling is not necessary for NASH pathogenesis in preclinical models and targeting this pathway alone may not be an effective therapeutic approach to ameliorate the disease progression in NASH patients.

Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma.

Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)-dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2-driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.

Inhibition of miR-99a-5p prevents allergen-driven airway exacerbations without compromising type-2 memory responses in the intestine following helminth infection.

Acute exacerbations (AE) of asthma, remain one of the biggest concerns for patients living with asthma. As such, identifying the causes, the molecular mechanisms involved and new therapeutic interventions to prevent AE is a high priority. Immunity to intestinal helminths involves the reactivation of type-2 immune responses leading to smooth muscle contraction and mucus hypersecretion-physiological processes very similar to acute exacerbations in the airways following allergen exposure. In this study, we employed a murine model of intestinal helminth infection, using Heligmosomoides polygyrus, to identify miRNAs during active expulsion, as a system for the identification of miRNAs that may contribute to AE in the airways. Concomitant with type-2 immunity and expulsion of H. polygyrus, we identified miR-99a-5p, miR-148a-3p and miR-155-5p that were differentially regulated. Systemic inhibition of these miRNAs, alone or in combination, had minimal impact on expulsion of H. polygyrus, but inhibition of miR-99a-5p or miR-155-5p significantly reduced house dust mite (HDM)-driven acute inflammation, modelling human acute exacerbations. Immunological, pathological and transcriptional analysis identified that miR-155-5p or miR-99a-5p contribute significantly to HDM-driven AE and that transient inhibition of these miRNAs may provide relief from allergen-driven AE, without compromising anti-helminth immunity in the gut.

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.