TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell–mediated Inflammation via IL-27–Producing Interstitial Macrophages

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

doi:10.1165/rcmb.2021-0042oc

Cited by 12 publications

(12 citation statements)

References 44 publications

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“…For example, HLA genes, critical for antigen presentation functions in DC and B-cells among others 57 are much more strongly expressed in CD34, than iPSC cells. Similarly, genes found in monocytes (MNDA, CSF1R and CCR1) 58 , 59 , mast cells (MCEMP1) 57 , 60 , B-cells (CD37) 61 and M2 MCs (CCL24) 47 , 55 were all present in CD34+ populations while absent in iPSC derived. These differences indicate further diversity within the CD34+ derived cells, but more importantly indicate a competency for certain myeloid functions and responses in these cells that may not be captured from iPSC derived.…”

Section: Discussionmentioning

confidence: 91%

“…Of note, was the identification of the DC2 population, which unlike DC1 cells did not display antigen presentation cell gene expression, such as HLA genes and CD74, typical of DCs. These DC2 cells with expression of CCL22 and FABP4 are more reliably identified as M2 like MCs, typically observed in vitro with differentiation in the presence of type 2 cytokines such as IL-4 47 , 55 . Indeed, the iDC protocol uses IL-4 in the final differentiation steps in our study and the identification of DC1 APC and DC M2-like cells further supports the successful implementation of these protocols to generate mature myeloid cells from IPSCs.…”

Section: Discussionmentioning

confidence: 95%

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Induced pluripotent and CD34+ stem cell derived myeloid cells display differential responses to particle and dust mite exposure

Fransen¹,

Leonard²

2023

Sci Rep

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Myeloid cells form an essential component of initial responses to environmental hazards and toxic exposures. The ability to model these responses in vitro is central to efforts tasked with identifying hazardous materials and understanding mechanisms of injury and disease. Induced pluripotent stem cell (iPSC) derived cells have been suggested as alternatives to more established primary cell testing systems for these purposes. iPSC derived macrophage and dendritic like cells were compared to CD34+ haematopoietic stem cell derived populations using transcriptomic analysis. Using single cell sequencing-based characterisation of iPSC derived myeloid cells, we identified transitional, mature and M2 like macrophages as well as dendritic like antigen presenting cells and fibrocytes. Direct transcriptomic comparisons between iPSC and CD34+ cell derived populations revealed higher expression of myeloid differentiation genes such as MNDA, CSF1R and CSF2RB in CD34+ cells, while iPSC populations had higher fibroblastic and proliferative markers. Exposure of differentiated macrophage populations to nanoparticle alone or in combination with dust mite, resulted in differential gene expression on combination only, with responses markedly absent in iPSC compared to CD34+ derived cells. The lack of responsiveness in iPSC derived cells may be attributable to lower levels of dust mite component receptors CD14, TLR4, CLEC7A and CD36. In summary, iPSC derived myeloid cells display typical characteristics of immune cells but may lack a fully mature phenotype to adequately respond to environmental exposures.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Induced pluripotent and CD34+ stem cell derived myeloid cells display differential responses to particle and dust mite exposure

Fransen¹,

Leonard²

2023

Sci Rep

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“…TLR7 activation increases IFN-λ receptor mRNA expression in PBMCs ( 124 ). Furthermore, a TLR7 agonist has been reported to inhibit ILC2-dependent airway inflammation through interstitial macrophages producing IL-27 in a mouse model ( 125 ). Another potential approach is TLR3 agonism.…”

Section: Possible Treatment Strategies For Suppressing Viral Infectio...mentioning

confidence: 99%

Innate Immune Responses by Respiratory Viruses, Including Rhinovirus, During Asthma Exacerbation

Nakagome

Nagata

2022

Front. Immunol.

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Viral infection, especially with rhinovirus (RV), is a major cause of asthma exacerbation. The production of anti-viral cytokines such as interferon (IFN)-β and IFN-α from epithelial cells or dendritic cells is lower in patients with asthma or those with high IgE, which can contribute to viral-induced exacerbated disease in these patients. As for virus-related factors, RV species C (RV-C) induces more exacerbated disease than other RVs, including RV-B. Neutrophils activated by viral infection can induce eosinophilic airway inflammation through different mechanisms. Furthermore, virus-induced or virus-related proteins can directly activate eosinophils. For example, CXCL10, which is upregulated during viral infection, activates eosinophils in vitro. The role of innate immune responses, especially type-2 innate lymphoid cells (ILC2) and epithelial cell-related cytokines including IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), in the development of viral-induced airway inflammation has recently been established. For example, RV infection induces the expression of IL-33 or IL-25, or increases the ratio of ILC2 in the asthmatic airway, which is correlated with the severity of exacerbation. A mouse model has further demonstrated that virus-induced mucous metaplasia and ILC2 expansion are suppressed by antagonizing or deleting IL-33, IL-25, or TSLP. For treatment, IFNs including IFN-β suppress not only viral replication but also ILC2 activation in vitro. Agonists of toll-like receptor (TLR) 3 or 7 can induce IFNs, which can then suppress viral replication and ILC2 activation. Therefore, if delivered in the airway, IFNs or TLR agonists could become innovative treatments for virus-induced asthma exacerbation.

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“…Toll-like receptors (TLRs) recognize components of viruses and bacteria to trigger an innate immune response. R848, a TLR7 agonist, stimulated IL-33-induced interstitial macrophages (IMs) to attenuate ILC2-mediated airway eosinophilic inflammation through IM-derived IL-27 ( 49 ), which suppressed the proliferation and type 2 cytokine production of murine and human ILC2s ( 50 , 51 ). Other TLR7 agonists, AZD8848 and GSK2245035, have been evaluated as therapeutic agents in clinical trials for asthma.…”

Section: The Therapeutic Potential Of Targeting the Interaction Betwe...mentioning

confidence: 99%

The Therapeutic Potential for Targeting Group 2 Innate Lymphoid Cells in Asthma

Matsuyama

Dotake

et al. 2022

Front. Immunol.

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T helper type 2 cells (Th2 cells) and group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma, including airway eosinophilic inflammation. ILC2s are activated by epithelial-derived cytokines [interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP)] from airway epithelial cells, leading to the release of high amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s induce airway inflammation in an antigen-independent manner, and ILC2s are considered to be involved in the pathogenesis of asthma exacerbation. Furthermore, ILC2 activation might also confer steroid resistance. Many recent studies in humans and mice are increasingly demonstrating that the function of ILC2s is regulated not just by epithelial-derived cytokines but by a variety of cytokines and mediators derived from innate immune cells. Furthermore, the biologics targeting these cytokines and/or their receptors have been shown to reduce asthma exacerbations and improve lung function and quality of life in asthmatics. This article reviews the current treatment landscape for type 2 airway inflammation in asthma and discusses the therapeutic potential for targeting ILC2s.

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TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell–mediated Inflammation via IL-27–Producing Interstitial Macrophages

Cited by 12 publications

References 44 publications

Induced pluripotent and CD34+ stem cell derived myeloid cells display differential responses to particle and dust mite exposure

Induced pluripotent and CD34+ stem cell derived myeloid cells display differential responses to particle and dust mite exposure

Innate Immune Responses by Respiratory Viruses, Including Rhinovirus, During Asthma Exacerbation

The Therapeutic Potential for Targeting Group 2 Innate Lymphoid Cells in Asthma

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