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

Abstract

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.

Innate lymphoid cell composition associates with COVID‐19 disease severity

“…We have previously reported increased ILC2 frequencies in the intestine of patients with inflammatory bowel disease 17 and in the lungs of patients with asthma, 49 likely due to their influx from the circulation. In line with this, it is possible that the lower ILC frequencies observed in severe as compared with moderate COVID‐19 patients could indicate potential trafficking of ILC2 to inflamed infection sites as previously described in asthma 49 and cystic fibrosis 50 . In striking resemblance with the latter study, we observed the lowest frequencies of ILC2 in patients with the highest serum levels of CCL20, and reduced frequencies of CCR6 + ILC2 in COVID‐19 patients.…”

“…In line with this, it is possible that the lower ILC frequencies observed in severe as compared with moderate COVID-19 patients could indicate potential trafficking of ILC2 to inflamed infection sites as previously described in asthma 49 and cystic fibrosis. 50 In striking resemblance with the latter study, we observed the lowest frequencies of ILC2 in patients with the highest serum levels of CCL20, and reduced frequencies of CCR6 + ILC2 in COVID-19 patients. Hence, our data point towards a role for CCL20mediated recruitment of CCR6 + ILC2 to the lung of COVID-19 patients, where they could contribute to fibrosis.…”

“…In striking resemblance with the latter study, we observed the lowest frequencies of ILC2 in patients with the highest serum levels of CCL20, and reduced frequencies of CCR6 + ILC2 in COVID‐19 patients. Hence, our data point towards a role for CCL20‐mediated recruitment of CCR6 + ILC2 to the lung of COVID‐19 patients, where they could contribute to fibrosis 50 . To exhaust this and other possible roles for ILC2 in COVID‐19, further studies at the tissue level are required.…”

“…Hence, our data point towards a role for CCL20mediated recruitment of CCR6 + ILC2 to the lung of COVID-19 patients, where they could contribute to fibrosis. 50 To exhaust this and other possible roles for ILC2 in COVID-19, further studies at the tissue level are required.…”

Proteomic Characterization, Biodistribution, and Functional Studies of Immune-Therapeutic Exosomes: Implications for Inflammatory Lung Diseases

“…Chemokine receptors and integrins and their binding partners shape the homing patterns of cells and ostensibly, EXO in the body (48). Of particular note are the chemotactic and adhesion factors identified in reg DCs EXO (Figure 6), including CCR6, CCR7, CXCR2, Integrin alpha-M (CD11b), Integrin beta-1 (CD29), CD47, Integrin alpha-1 (CD49a), ICAM-1(CD54), integrin beta-2, integrin alpha-5, and integrin alpha-L (LFA1) (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). CCR7 (50) mediates blood-derived lymphocyte trafficking to bronchial associated lymphoid tissue while CXCR2 directs neutrophil recruitment to the lungs (51).…”