TLR7 agonist suppresses group 2 innate lymphoid cell–mediated inflammation via IL-27–producing interstitial macrophages

Shinichi Okuzumi, Jun Miyata, Hiroki Kabata, Takao Mochimaru, Shizuko Kagawa, Katsunori Masaki, Misato Irie, Hideaki Morita, Koichi Fukunaga

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33–induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33–induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33–induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1–deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33–induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.

Original languageEnglish
Pages (from-to)309-318
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume65
Issue number3
DOIs
Publication statusPublished - 2021 Sep

Keywords

  • Asthma
  • IL-33
  • ILC2
  • Interstitial macrophage
  • R848

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'TLR7 agonist suppresses group 2 innate lymphoid cell–mediated inflammation via IL-27–producing interstitial macrophages'. Together they form a unique fingerprint.

Cite this