Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the TH2 cytokines ...IL-5 and IL-13, which promote acute asthma exacerbation. Short-chain fatty acids (SCFAs) have been shown to attenuate T cell–mediated allergic airway inflammation. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.
We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
We assessed the role of SCFAs in regulating survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in the ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.
We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma.
Display omitted
Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet ...for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.
Abstract
A dysregulated type 2 immune response is one of the fundamental causes of allergic asthma. Although Th2 cells are undoubtedly central to the pathogenesis of allergic asthma, the discovery of ...group 2 innate lymphoid cells (ILC2s) has added another layer of complexity to the etiology of this chronic disease. Through their inherent innate type 2 responses, ILC2s not only contribute to the initiation of airway inflammation but also orchestrate the recruitment and activation of other members of innate and adaptive immunity, further amplifying the inflammatory response. Moreover, ILC2s exhibit substantial cytokine plasticity, as evidenced by their ability to produce type 1- or type 17-associated cytokines under appropriate conditions, underscoring their potential contribution to nonallergic, neutrophilic asthma. Thus, understanding the mechanisms of ILC2 functions is pertinent. In this review, we present an overview of the current knowledge on ILC2s in asthma and the regulatory factors that modulate lung ILC2 functions in various experimental mouse models of asthma and in humans.
Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and ...asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (T(H)2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)-IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
Background
Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL‐33 is elevated and promotes immune cell activation, leading to the development ...of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL‐33‐activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection‐triggered pathophysiology.
Methods
The role of IL‐33/ILC2 axis in RSV‐induced AHR inflammation and eosinophilia were evaluated in the IL‐33‐deficient and YetCre‐13 Rosa‐DTA mice. Myeloid‐specific, IL‐33‐deficient or ST2‐deficient mice were employed to examine the role of IL‐33 and ST2 signaling in myeloid cells.
Results
We found that IL‐33‐activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2‐derived IL‐13 was sufficient for RSV‐driven AHR, since reconstitution of wild‐type ILC2 rescued RSV‐driven AHR in IL‐13‐deficient mice. Meanwhile, myeloid cell‐derived IL‐33 was required for airway inflammation, ST2+ myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL‐33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL‐33 signaling.
Conclusions
This study highlights the importance of IL‐33‐activated ILC2s in mediating RSV‐triggered AHR and eosinophilia. In addition, IL‐33 signaling in myeloid cells is crucial for airway inflammation.
Respiratory syncytial virus induces ILC2 to produce IL‐5 and IL‐13 through IL‐33, which is crucial for the development of airway hyperreactivity and airway inflammation. Myeloid cell‐derived IL‐33 and suppression of tumorigenicity 2‐positive myeloid cells contribute to cytokine production and cellular inflammation in airway. Both ILC2 and myeloid cell IL‐33 signaling contribute to local and peripheral eosinophilia.
Abstract
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is ...controversial. Here, we show that Treg cell development is normal in mice with Foxp3-specific knockout (KO) of HIF-1α or HIF-2α. However, HIF-2α-KO (but not HIF-1α-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2α-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2α and HIF-1α, and that HIF-2α represses HIF-1α expression. HIF-1α is upregulated in HIF-2α-KO Treg cells and further deletion of HIF-1α restores the inhibitory function of HIF-2α-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells.
A near-infrared light-responsive drug delivery platform based on Au–Ag nanorods (Au–Ag NRs) coated with DNA cross-linked polymeric shells was constructed. DNA complementarity has been applied to ...develop a polyacrylamide-based sol–gel transition system to encapsulate anticancer drugs into the gel scaffold. The Au–Ag NR-based nanogels can also be readily functionalized with targeting moieties, such as aptamers, for specific recognition of tumor cells. When exposed to NIR irradiation, the photothermal effect of the Au–Ag NRs leads to a rapid rise in the temperature of the surrounding gel, resulting in the fast release of the encapsulated payload with high controllability. In vitro study confirmed that aptamer-functionalized nanogels can be used as drug carriers for targeted drug delivery with remote control capability by NIR light with high spatial/temporal resolution.
Group 2 innate lymphoid cells (ILC2s) are important mediators of allergic asthma. Bacterial components, such as unmethylated CpG DNA, a Toll-like receptor (TLR) 9 agonist, are known to possess ...beneficial immunomodulatory effects in patients with T cell–mediated chronic asthma. However, their roles in regulating ILC2s remain unclear.
We sought to determine the role of TLR9 activation in regulating ILC2 function and to evaluate the therapeutic utility of an immunomodulatory microparticle containing natural TLR9 ligand (MIS416).
We evaluated the immunomodulatory effects of CpG A in IL-33–induced airway hyperreactivity (AHR) and airway inflammation. The roles of interferons were examined in vivo and in vitro by using signal transducer and activator of transcription 1 (Stat1)−/− mice and neutralizing antibodies against IFN-γ and IFN-α/β receptor subunit 1, and their cellular sources were identified. The therapeutic utility of MIS416 was investigated in the Alternaria alternata model of allergic asthma and in humanized NSG mice.
We show that TLR9 activation by CpG A suppresses IL-33–mediated AHR and airway inflammation through inhibition of ILC2s. Activation of TLR9 leads to production of IFN-α, which drives IFN-γ production by natural killer cells. Importantly, IFN-γ is essential for TLR9-driven suppression, and IFN-α cannot compensate for impaired IFN-γ signaling. We further show that IFN-γ directly inhibits ILC2 function through a STAT1-dependent mechanism. Finally, we demonstrate the therapeutic potential of MIS416 in A alternata–induced airway inflammation and validated these findings in human subjects.
TLR9 activation alleviates ILC2-driven AHR and airway inflammation through direct suppression of cell function. Microparticle-based delivery of TLR9 ligands might serve as a therapeutic strategy for asthma treatment.
Display omitted
Background Asthma has been considered an immunologic disease mediated by TH 2 cells and adaptive immunity. However, clinical and experimental observations suggest that additional pathways might ...regulate asthma, particularly in its nonallergic forms, such as asthma associated with air pollution, stress, obesity, and infection. Objectives Our goal was to understand TH 2 cell–independent conditions that might lead to airway hyperreactivity (AHR), a cardinal feature of asthma. Methods We examined a murine model of experimental asthma in which AHR was induced with glycolipid antigens, which activate natural killer T (NKT) cells. Results In this model AHR developed rapidly when mice were treated with NKT cell–activating glycolipid antigens, even in the absence of conventional CD4+ T cells. The activated NKT cells directly induced alveolar macrophages to produce IL-33, which in turn activated NKT cells, as well as natural helper cells, a newly described non-T, non-B, innate lymphoid cell type, to increase production of IL-13. Surprisingly, this glycolipid-induced AHR pathway required not only IL-13 but also IL-33 and its receptor, ST2, because it was blocked by an anti-ST2 mAb and was greatly reduced in ST2−/− mice. When adoptively transferred into IL-13−/− mice, both wild-type natural helper cells and NKT cells were sufficient for the development of glycolipid-induced AHR. Conclusion Because plant pollens, house dust, and some bacteria contain glycolipids that can directly activate NKT cells, these studies suggest that AHR and asthma can fully develop or be greatly enhanced through innate immune mechanisms involving IL-33, natural helper cells, and NKT cells.
Atopic dermatitis (AD) is an inflammatory skin disease caused by the disruption of skin barrier, and is dominated by the type 2 immune responses. Patients with AD have a high risk of developing
...infection. Interleukin-33 (IL-33), an alarmin, has been implicated in the pathophysiology of AD development. Butyrate, a short chain fatty acid known to be produced from the fermentation of glycerol by the commensal skin bacterium,
, has been reported to possess antimicrobial and anti-inflammatory properties that suppress inflammatory dermatoses. However, little is known about the effects of butyrate on dermal IL-33 expression and associated immune response in
-aggravated skin inflammation in the context of AD. To decipher the underlying mechanism, we established an AD-like mouse model with epidermal barrier disruption by delipidizing the dorsal skin to induce AD-like pathophysiology, followed by the epicutaneous application of
and butyrate. We discovered that
infection exacerbated IL-33 release from keratinocytes and aggravated dermal leukocyte infiltration and IL-13 expression. Moreover, we showed that butyrate could attenuate
-aggravated skin inflammation with decreased IL-33, IL-13, and leukocyte infiltration in the skin. Mechanistically, we demonstrated that butyrate suppressed IL-33 expression and ameliorated skin inflammation through histone deacetylase 3 (HDAC3) inhibition. Overall, our findings revealed the potential positive effect of butyrate in controlling inflammatory skin conditions in AD aggravated by
infection.