Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by an RORγt inverse agonist

Whitehead, Gregory S.; Kang, Hong Soon; Thomas, Seddon Y.; Medvedev, Alexander V.; Karcz, Tadeusz; Izumi, Gentaro; Nakano, Keiko; Makarov, Sergei S.; Nakano, Hideki; Jetten, Anton M.; Cook, Donald N.

doi:10.1172/jci.insight.125528

Cited by 20 publications

(16 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was associated with improvements in both AHR and pulmonary neutrophilia, although when individual Th17-associated cytokines were instilled into naïve mouse lungs, IL-17 was associated with neutrophil recruitment, whereas IL-22 was required in combination with IL-17 to drive AHR. Similar findings have also been reported with a RORγt inverse agonist [39] although the clinical significance was not explored. In this study we also demonstrate that these effects are linked to 80% pathway engagement and trough plasma concentrations that cover cellular IC 50 indicating that these are effects are specific and on-target.…”

Section: Discussionsupporting

confidence: 75%

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

et al. 2021

View full text Add to dashboard Cite

Background RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma. Methods IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Results We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells. Conclusion These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.

show abstract

Section: Discussionsupporting

confidence: 75%

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Another member of the ROR family, RORγt, is reported to drive the allergic airway inflammation toward a steroid-insensitive neutrophilic phenotype ( 190 ). Inhibition of RORγt also led to suppression of allergic airway hyperresponsiveness and pulmonary neutrophilia in a murine model of asthma ( 191 , 192 ) ( Figure 3C ).…”

Section: Nuclear Receptors In Asthmamentioning

confidence: 89%

Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment

Tiwari

Gupta

2021

Front. Immunol.

View full text Add to dashboard Cite

The escalation in living standards and adoption of ‘Western lifestyle’ has an allied effect on the increased allergy and asthma burden in both developed and developing countries. Current scientific reports bespeak an association between allergic diseases and metabolic dysfunction; hinting toward the critical requirement of organized lifestyle and dietary habits. The ubiquitous nuclear receptors (NRs) translate metabolic stimuli into gene regulatory signals, integrating diet inflences to overall developmental and physiological processes. As a consequence of such promising attributes, nuclear receptors have historically been at the cutting edge of pharmacy world. This review discusses the recent findings that feature the cardinal importance of nuclear receptors and how they can be instrumental in modulating current asthma pharmacology. Further, it highlights a possible future employment of therapy involving dietary supplements and synthetic ligands that would engage NRs and aid in eliminating both asthma and linked comorbidities. Therefore, uncovering new and evolving roles through analysis of genomic changes would represent a feasible approach in both prevention and alleviation of asthma.

show abstract

“…Although asthma has been first considered as a Th2mediated disease, the pro-inflammatory Th17 cells (the major source of IL-17A) have recently focused attention. 3,4 Th17 and regulatory T cells (Treg) are inversely modulated in asthma, as Th17 cells are increased and Treg cells decreased both in the peripheral circulation and in induced sputum (IS). 5 Through IL-17A, Th17 cells contribute to pulmonary recruitment and accumulation of neutrophils and macrophages.…”

Section: Introductionmentioning

confidence: 99%

“…5 Through IL-17A, Th17 cells contribute to pulmonary recruitment and accumulation of neutrophils and macrophages. 4 However, anti-TNF-α and anti-IL-17A failed to show efficacy in asthma patients 6 emphasizing the need to establish the role of other Th17 cytokines such as IL-26. 7 An up-regulation of IL-26 has been previously reported in paediatric asthma.…”

Section: Introductionmentioning

confidence: 99%

<p>Sputum IL-26 Is Overexpressed in Severe Asthma and Induces Proinflammatory Cytokine Production and Th17 Cell Generation: A Case–Control Study of Women</p>

Louhaichi¹,

Mlika²,

Hamdi³

et al. 2020

JAA

View full text Add to dashboard Cite

Objective: Asthma inflammation is a complex pathway involving numerous mediators. Interleukin-26 (IL-26), a member of the IL-10 cytokine family, is abundant in human airways and induces the production of proinflammatory cytokines. Our aim was to investigate the possible role of IL-26 in severe asthma. We analysed the expression of IL-26 in severe asthma both in peripheral blood and induced sputum. Patients and Methods: A total of 50 adult women with severe asthma were recruited and compared to 30 healthy controls (HC). Serum and sputum fluid (SF) levels of IL-26 and IL-17 were defined by ELISA. IL-26 mRNA expression and IL-26 protein were analysed using RT-PCR and Western blot. In vitro, we studied the effect of recombinant IL-26 (rIL-26) and SF-IL-26 on cultured CD4 + T cells and monocytes, comparing patients and controls. Results: Concentrations of IL-26 are higher in serum and induced sputum of asthmatic patients than in HC. Moreover, IL-26 protein and mRNA expression were significantly elevated in asthma sputum cells compared to PBMCs. We observed a positive correlation between body mass index (BMI) and sputum fluid IL-26, while the correlation between IL-26 and lung function tests (FEV1% and FEV1/FVC ratio) was negative. IL-17A was highly expressed in SF and correlated positively with IL-26. In patients' sputum IL-26 and IL-17A were significantly associated with neutrophils. Stimulation of cultured CD4 + T cells with monocytes by recombinant IL-26 promoted the generation of RORγt + Th17 + cells inducing the production of IL-17A, IL-1β, IL-6 and TNF-α cytokines. IL-26 expressed in SF was biologically active and induced IL-17 secretion in the presence of IL-1β and IL-6 cytokines. Conclusion: These findings show that IL-26 is highly produced in asthmatic sputum, induces pro-inflammatory cytokine secretion by monocytes/macrophages, and favours Th17 cell generation. IL-26 thereby appears as a novel pro-inflammatory cytokine, produced locally in the airways that may constitute a promising target to treat asthma inflammatory process.

show abstract

Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by an RORγt inverse agonist

Cited by 20 publications

References 56 publications

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment

<p>Sputum IL-26 Is Overexpressed in Severe Asthma and Induces Proinflammatory Cytokine Production and Th17 Cell Generation: A Case–Control Study of Women</p>

Contact Info

Product

Resources

About