Trained immunity in allergic asthma

The complex symptomology of allergic bronchial asthma arises from chronic inflammation of the airways. For decades it was commonly believed that this inflammation is centrally orchestrated and maintained by the adaptive immune system, namely, by T cells (eg, TH2, TH17 cells, and regulatory T cells) and B cells, which are capable of not only differentiating between "self "and "non-self" but also creating an immunologic memory of "non-self." Although these findings remain fully valid, the view that these 2 abilities are exclusive attributes of the adaptive immune system had to be changed because of the discovery in the late 1990s of Toll-like receptors, which enable cells of the innate immune system to recognize multiple microorganisms. Beyond that, a little more than 10 years ago functions related to an immunologic memory were also described for innate immune cells and termed trained immunity. In contrast to the immune memory of the adaptive immune system, trained immunity does not involve genomic rearrangements but is instead achieved exclusively by regulatory epigenetic mechanisms such as DNA methylation, histone modifications, and transcription of noncoding RNAs, as well as by metabolic reprogramming, that produce a prolonged state of enhanced or diminished responsiveness to infection and inflammation, as induced by allergens, air pollutants, or change of diet. Subsequently, the mechanisms underlying formation of trained immunity and its functions have been described in detail for monocytes, macrophages, and also dendritic cells. More recently, such functions have also been attributed to natural killer cells, type 2 innate lymphoid tissue cells, mast cells, and basophil subpopulations, which are critically involved in the regulation of type 2 immune responses.1Hartung F. Esser-von Bieren J. Trained immunity in type 2 immune responses.Muc Immunol. 2022; 15: 1158-1169Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Concerning asthma research, the identification of trained immunity has the potential to shed more light on the 2 central pathogenetic issues that still remain to be clarified, namely, the processes leading to initiation of the disease and those leading to its progression. Already for decades, the hygiene hypothesis suggests protective influence of microbial exposures in early life on the development of allergic diseases such as asthma. A few years ago, Stein et al illustrated this effect in children from Amish and Hutterites families, which share genetic ancestry and lifestyles but differ by virtue of points of farming practices and thus, exposure to microbes, making it possible to attribute the effect to innate immunity.2Stein M.M. Hrusch C.L. Gozdz J. Igartua C. Pivniouk V. Murray S.E. et al.Innate immunity and asthma risk in Amish and Hutterite farm children.N Engl J Med. 2016; 375: 411-421Crossref PubMed Scopus (670) Google Scholar Whether such a protective effect is indeed mediated through epigenetic mechanisms that result in trained immunity remains to be investigated. However, Nieto et al3Nieto A. Mazón A. Nieto M. Calderón R. Calaforra S. Selva B. et al.Bacterial mucosal immunotherapy with MV130 prevents recurrent wheezing in children: a randomized, double-blind, placebo-controlled clinical trial.Am J Respir Crit Care Med. 2021; 204: 462-472Crossref PubMed Scopus (33) Google Scholar recently provided evidence that this could really be the case. In this placebo-controlled clinical trial, 120 preschool children at risk of infection-associated recurrent wheeze were treated for 6 months with a mixture of 6 heat-inactivated common bacterial pathogens that were delivered orally. This treatment led to significantly fewer wheezing attacks and to a reduction in symptoms and medication scores. Remarkably, the effects lasted for up to 6 months after treatment discontinuation.3Nieto A. Mazón A. Nieto M. Calderón R. Calaforra S. Selva B. et al.Bacterial mucosal immunotherapy with MV130 prevents recurrent wheezing in children: a randomized, double-blind, placebo-controlled clinical trial.Am J Respir Crit Care Med. 2021; 204: 462-472Crossref PubMed Scopus (33) Google Scholar Whether exposure to microbes shapes the immune system to increase or reduce susceptibility to asthma development appears to depend not only on the time point but also on the pattern or combination of microbes. Thus, recurrent exposure to distinct bacteria such as Moraxella catarrhalis or Haemophilus influenzae, and especially infection with respiratory viruses such as respiratory syncytial virus or rhinovirus, increases the risk of asthma development in later life.4Jartti T. Gern J.E. Role of viral infections in the development and exacerbation of asthma in children.J Allergy Clin Immunol. 2017; 140: 895-906Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar The first experimental example of an infection-induced protective effect against the development of asthma that is based on long-term programming of innate immune cells was provided by Machiels et al.5Machiels B. Dourcy M. Xiao X. Javaux J. Mesnil C. Sabatel C. et al.A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.Nat Immunol. 2017; 18: 1310-1320Crossref PubMed Scopus (143) Google Scholar Their study demonstrated that pulmonary infection with murid herpesvirus 4 (MuHV-4) protected against induction of house dust mite (HDM)-induced experimental allergic asthma (EAA) (HDM-EAA) 30 days after infection. Machiels et al5Machiels B. Dourcy M. Xiao X. Javaux J. Mesnil C. Sabatel C. et al.A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.Nat Immunol. 2017; 18: 1310-1320Crossref PubMed Scopus (143) Google Scholar showed in detail that on the one hand, MuHV-4 infection led to reduced expression of costimulatory molecules by migratory dendritic cells and thus to a reduced ability to induce effector TH2 cell responses to HDM. On the other hand, pulmonary MuHV-4 infection induced the death of resident embryonic alveolar macrophages and the recruitment of bone marrow–derived (BMD) monocytes that produce more IL-10 than produced by mock-infected mice. Subsequently, Machiels et al5Machiels B. Dourcy M. Xiao X. Javaux J. Mesnil C. Sabatel C. et al.A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.Nat Immunol. 2017; 18: 1310-1320Crossref PubMed Scopus (143) Google Scholar used different cell transfer experiments to demonstrate that such BMD monocytes persist in alveoli for up to 28 days and suggested that under MuHV-4 infection resident embryonic alveolar macrophages are replaced by recruited monocytes with a regulatory profile as a major mechanism underlying the long-term training of lung immunity after infection. In contrast, 2 recent studies demonstrated that trained immunity effects can also favor the development of experimental asthma in mice. Thus, following the observation of an increasing asthma prevalence after various epidemics of enterovirus 71 (EV-A71) in Taiwan after 1998, Chen et al aimed to investigate the effect of extrapulmonary, neonatal EV-A71 infection on the development of HDM-EAA in mice. They found that intraperitoneal EV-A71 infection at the early age of 14 days led to innate immune training of macrophages that adopted a proinflammatory status and released more IL-6, TNF, and CCL17. Indeed, this status persisted over at least 3 weeks and could be blocked by 2-DG, a glucose molecule that is supposed to block further glycolysis in cells participating in trained immunity. When mice were subjected to HDM-EAA after infection, they not only displayed increased titers of HDM-specific IgE but also exhibited amplified disease pathology. Comparable results could be observed in naive mice that received EV-A71–trained BMD macrophages by adoptive transfer before induction of HDM-EAA, suggesting that trained macrophages following extrapulmonary enterovirus infection could favor the development of allergic asthma in later life.6Chen P.C. Shao Y.T. Hsieh M.H. Kao H.F. Kuo W.S. Wang S.M. et al.Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity.Cell Mol Immunol. 2021; 18: 472-483Crossref PubMed Scopus (7) Google Scholar Also, Lechner et al7Lechner A. Henkel F.D.R. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar focused on the role of macrophages in the pathogenesis of allergic bronchial asthma because they had observed that monocyte-derived macrophages of patients with asthma and HDM allergy as well as BMD macrophages from mice with HDM-EAA display persistently upregulated inflammatory genes, including type 2 (T2) inflammatory chemokines. They further showed that macrophages from these mice initially revealed a T2 imprint that shifted toward a classical proinflammatory training as characterized by expression of IL-6 and CCL17 over time. This indicates that HDM, which naturally contains microbial compounds such as LPS, and HDM-induced inflammation elicit the activated proinflammatory macrophage phenotype.7Lechner A. Henkel F.D.R. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Both studies suggest that innate immune training, which can be interpreted as an adaption of immune cells to strengthen responses to future infections, increases the risk of unintentional promotion of unwanted inflammation by the enhanced release of proinflammatory cytokines (eg, IL-1, IL-6, TNF), chemokines (eg, CCL17), and lipid mediators (eg, cysteinyl leukotrienes). These 3 studies that focused on macrophages are among the earliest to mechanistically investigate the contribution of trained immunity to the pathogenesis of allergic asthma. As already mentioned, from the beginning these cells were at the center of study of trained immunity, and shortly afterward, studies of other cells, including dendritic cells, type 2 innate lymphoid tissue cells, and natural killer cells, followed. However, the question of whether structural cells that carry out innate immune functions such as those of airway epithelial cells could also develop an innate immune memory and have an impact on disease development on their own remains largely unresolved. Of course, these cells are not able to roam through vessels and tissues as classic immune cells can and instead constitute the barrier between the body and its environment. However, because these cells express a broad array of pattern recognition receptors enabling them to react to microbial compounds and because they are often among the first cells to initiate acute inflammatory reactions, even the most conservative immunologists cannot deny that they contribute essentially to the defense of our body. And if we talk about asthma pathogenesis and the impact of viral infection and exposure to microbial compounds, allergens, and air pollution on this process, the role of airway epithelial cells gains even more weight. As part of the epithelial-mesenchymal trophic unit they are at the center of inflammation (and its cytokine milieu) and airway remodeling; they represent the target cells for most of the respiratory viruses implemented in the development and exacerbation of asthma; and they are capable of releasing alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin, which have been shown to initiate T2 immune responses.8Frey A. Lunding L.P. Ehlers J.C. Weckmann M. Zissler U.M. Wegmann M. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis.Front Immunol. 2020; 11: 761Crossref PubMed Scopus (99) Google Scholar A first hint toward innate training and, thus, creation of an inflammatory memory in airway epithelial cells was provided by Ordovas-Montanes et al,9Ordovas-Montanes J. Dwyer D.F. Nyquist S.K. Buchheit K.M. Vukovic M. Deb C. et al.Allergic inflammatory memory in human respiratory epithelial progenitor cells.Nature. 2018; 560: 649-654Crossref PubMed Scopus (297) Google Scholar who used parallel single-cell RNA sequencing of nasal epithelial cells from patients with chronic rhinosinusitis. Here, they not only defined expression signatures of distinct cell types but also demonstrated that basal cells retain an intrinsic memory of exposure to TH2-type cytokines when cultured ex vivo, suggesting that they may contribute to disease persistence by serving as repositories for allergic memories. Subsequently, a brief report by Bigot et al10Bigot J. Guillot L. Guitard J. Ruffin M. Corvol H. Chignard M. et al.Respiratory epithelial cells can remember infection: a proof-of-concept study.J Infect Dis. 2020; 221: 1000-1005PubMed Google Scholar used homologous and heterologous in vitro exposure to different bacteria and bacterial compounds, respectively, to demonstrate that respiratory epithelial cells indeed memorize a microbial contact and that this affects the response (eg, the release of proinflammatory cytokines such as IL-1 and IL-8) to the next stimulation. Hence, it depended on the combination of exposures to exacerbate or dampen this subsequent response—an outcome that resembled the findings of the aforementioned studies in murine macrophages in a simplified manner. Together, these works clearly demonstrate that trained immunity is involved in the pathogenesis of allergic asthma and may even play a decisive role: they demonstrated that cells carrying out innate immune functions develop and maintain a memory of an exposure to microbial compounds, viral infection, and subsequent inflammation, respectively, and that this memory could lead to or prevent allergic sensitization and airway inflammation and even have an impact on acute asthma exacerbations (depicted in Fig 1). Remarkably, this memory is not restricted to the compartment in which the imprinting encounter took place, so that training in the gut or peritoneum could also affect immune responses in the lung. Most of the factors described as being involved in trained immunity in asthma comprise proinflammatory mediators such as IL-1, IL-6, TNF, CCL17, and lipid mediators, which are also involved in nonallergic asthma as well as in other chronic inflammatory diseases of the lung, which underlines the putative impact of innate immune training on such disorders. Last but not least, these studies show that innate immune cells never stop learning and can be reprogrammed, either by the environment, leading to disease progression or—and this option has now become available—by a targeted approach to therapeutically interacting with trained immunity.