Group 2 Innate Lymphoid Cells in Human Respiratory Disorders

Ploeg, Esmee K. van der; Mascaro, Ana Carreras; Huylebroeck, Danny; Hendriks, Rudolf W.; Stadhouders, Ralph

doi:10.1159/000496212

Cited by 28 publications

(26 citation statements)

References 127 publications

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“…They are of particular importance for host defense at epithelial barrier surfaces (21), but also contribute to the systemic pool of circulating immune cells (22,23). Characterized by a type-2 cytokine profile and the expression of signature surface molecules (e.g., CD127 and CRTH2) (24,25) and transcription factors (e.g., GATA3) (26), group-2 ILCs (ILC2s) represent a predominant helper ILC population in the lung under steady state conditions (27,28). There they are preferentially located in direct proximity to the airway epithelium or accumulate within infected foci (27,29).…”

Section: Introductionmentioning

confidence: 99%

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

et al. 2020

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Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6 + ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.

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Section: Introductionmentioning

confidence: 99%

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

et al. 2020

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“…Whether ILCs can also be targeted specifically is unclear to date and requires further research. Based on our current knowledge, however, the partial functional redundancy between ILCs and Th cells under physiological conditions (26) and the crucial impact of mucosal ILCs on multiple inflammatory disorders (6,75) qualifies this innate cell type as an excellent therapeutic target with minimal adverse events (5,237).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

2020

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Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies.

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“…Upon allergen exposure, barrier epithelial cells in the lungs of susceptible individuals mount a proinflammatory response involving the secretion of chemokines, cytokines, and alarmins that induce activation of group 2 innate lymphoid cells and dendritic cells to mount a T helper 2-mediated (Th2-mediated) immune response (2,3). Disease hallmarks of allergic asthma can be attributed to cytokines that are produced by Th2 cells: IL-4 induces IgE class switching of B cells, IL-5 recruits eosinophils, and IL-13 provokes smooth muscle hyperreactivity, goblet cell hyperplasia, and mucus production (4).…”

Section: Introductionmentioning

confidence: 99%

Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress

Tindemans¹,

Schoonhoven²,

KleinJan³

et al. 2020

Journal of Clinical Investigation

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Group 2 Innate Lymphoid Cells in Human Respiratory Disorders

Cited by 28 publications

References 127 publications

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress

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