Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype

Tiotiu, Angélica; Kermani, Nazanin Zounemat; Badi, Yusef; Pavlidis, Stelios; Hansbro, Philip M.; Guo, Yike; Chung, Kian Fan; Adcock, Ian M.

doi:10.1111/all.14535

Cited by 28 publications

(29 citation statements)

References 42 publications

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“…This study demonstrated that macrophages provide a critical danger signal in response to allergen exposure, namely APOE, and through this mechanism enhance the adaptive inflammatory response to aeroallergens (165). Similar findings were also reported by Tiotiu et al, based on an analysis of sputum macrophages obtained from 104 asthmatics and 16 healthy volunteers in the U-BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes) asthma cohort (166). In this study, the gene signatures for differentially stimulated macrophages, i.e.…”

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmasupporting

confidence: 89%

“…It was found that, although macrophage numbers were significantly lower in severe asthmatics compared to mild/moderate asthmatics and healthy controls, the M2 signature was much higher in severely ill patients. Interestingly, macrophages from severe asthmatics were also enriched for eicosanoid biosynthesis and showed evidence of increased mitochondrial ROS production, implicating macrophages in the maintenance of inflammation and the induction of oxidative stress in cases of severe disease (166). Intriguingly, this study found significant changes in tissueresident macrophage signature enrichment according to asthma severity.…”

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 51%

“…It has been suggested that the dynamic polarization of lung tissue-resident macrophages during inflammation is highly dependent on mitochondrial activity, i.e. increased levels of oxidative phosphorylation early in the immune response facilitates cytokine expression and cell migration, whereas during the resolution phase, macrophages are considerably less active (166). The data from U-BIOPRED indicate that, in both healthy subjects and mild/moderate asthmatics, tissue-resident macrophages exist in a state of readiness, which is not unexpected given their exposure to the external environment.…”

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 99%

“…The data from U-BIOPRED indicate that, in both healthy subjects and mild/moderate asthmatics, tissue-resident macrophages exist in a state of readiness, which is not unexpected given their exposure to the external environment. However, this homeostasis breaks down in severe asthma, with evidence of increased expression of inflammatory mediators, in particular Th2 cytokines such as IL-4 and IL-13 (166). Clearly, gaining a deeper understanding of the functional diversity and plasticity of macrophages in allergic asthma will be important for developing more effective therapeutic strategies based on disease phenotype and allow for a more personalized medicine approach to the treatment of asthma.…”

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 99%

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Macrophages: The Good, the Bad, and the Gluttony

2021

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Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.

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Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmasupporting

confidence: 89%

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 51%

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 99%

Section: Lung Macrophage Diversity and Immune Regulation In Allergic Asthmamentioning

confidence: 99%

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Macrophages: The Good, the Bad, and the Gluttony

2021

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“…Macrophages. Lung macrophages play a pivotal role in asthma and COPD [ 111 , 112 ]. Macrophages are abundant in the lung and generate RONS to kill invading pathogens [ 113 , 114 , 115 ].…”

Section: Factors Contributing To Oxidative Stressmentioning

confidence: 99%

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

et al. 2021

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Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.

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