Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes

Chan, Yvonne R.; Chen, Kong; Duncan, Steven R.; Lathrop, Kira L.; Latoche, Joseph D.; Logar, Alison J.; Pociask, Derek; Wahlberg, Brendon; Ray, Prabir; Ray, Anuradha; Pilewski, Joseph M.; Kolls, Jay K.

doi:10.1016/j.jaci.2012.05.036

Cited by 66 publications

(70 citation statements)

References 72 publications

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“…3C). This is consistent with the human disease, as Th17 cells have been found to be elevated in the lung of CF patients (10). In turn, the increased number of Th17-producing lymphocytes in CF lungs may be driven by elevated levels of IP-10, which is a potent chemoattractant for T cells, monocytes/M⌽s, and natural killer (NK) cells, and has been associated with the CF lung exacerbations (30).…”

Section: Resultssupporting

confidence: 69%

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling

Bruscia

Zhang

Barone

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic fibrosis (CF) is caused by homozygous mutations of the CF transmembrane conductance regulator (CFTR) Cl− channel, which result in chronic pulmonary infection and inflammation, the major cause of morbidity and mortality. Although these processes are clearly related to each other, each is likely to contribute to the pathology differently. Understanding the contribution of each of these processes to the overall pathology has been difficult, because they are usually so intimately connected. Various CF mouse models have demonstrated abnormal immune responses compared with wild-type (WT) littermates when challenged with live bacteria or bacterial products acutely. However, these studies have not investigated the consequences of persistent inflammation on lung tissue in CF mice, which may better model the lung pathology in patients. We characterized the lung pathology and immune response of Cftr−/− (CF) and Cftr+/+ (WT) mice to chronic administration of Pseudomonas aeruginosa lipopolysaccharide (LPS). We show that, after long-term repeated LPS exposure, CF mice develop an abnormal and persistent immune response, which is associated with more robust structural changes in the lung than those observed in WT mice. Although CF mice and their WT littermates develop lung pathology after chronic exposure to LPS, the inflammation and damage resolve in WT mice. However, CF mice do not recover efficiently, and, as a consequence of their chronic inflammation, CF mice are more susceptible to morphological changes and lung remodeling. This study shows that chronic inflammation alone contributes significantly to aspects of CF lung pathology.

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Section: Resultssupporting

confidence: 69%

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling

Bruscia

Zhang

Barone

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Collectively, the lack of robust IL-17A and IL-22 production in the lungs of Cl 2 -exposed mice after microbial challenge suggests that a component of Cl 2 -induced immunosuppression is lower induction of soluble antimicrobial factors via the IL-17A and IL-22 axis. Since IL-17A and IL-22 are essential effector cytokines that coordinate the immune response to multiple lung pathogens, including A. fumigatus (26,61), influenza (33,46), Pseudomonas aeruginosa (15), Klebsiella pneumonia (4), and Staphylococcus aureus (17,32), our finding has broad implications for lung host defense mechanisms impaired by Cl 2 gas exposure (and potentially other agents that target the respiratory tract).…”

Section: Discussionmentioning

confidence: 90%

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Gessner¹,

Doran

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chlorine (Cl2) is a highly irritating and reactive gas with potential occupational and environmental hazards. Acute exposure to Cl2 induces severe epithelial damage, airway hyperreactivity, impaired alveolar fluid clearance, and pulmonary edema in the presence of heightened inflammation and significant neutrophil accumulation in the lungs. Herein, we investigated whether Cl2 exposure affected the lung antimicrobial immune response leading to increased susceptibility to opportunistic infections. Mice exposed to Cl2 and challenged intratracheally 24 h thereafter with the opportunistic mold Aspergillus fumigatus demonstrated an >500-fold increase in A. fumigatus lung burden 72 h postchallenge compared with A. fumigatus mice exposed to room air. Cl2-exposed A. fumigatus challenged mice also demonstrated significantly higher lung resistance following methacholine challenge and increased levels of plasma proteins (albumin and IgG) in the bronchoalveolar lavage fluid. Despite enhanced recruitment of inflammatory cells to the lungs of Cl2-exposed A. fumigatus challenged mice, these cells (>60% of which were neutrophils) demonstrated a profound impairment in generating superoxide. Significantly higher A. fumigatus burden in the lungs of Cl2 exposed mice correlated with enhanced production of IL-6, TNF-α, CXCL1, CCL2, and CCL3. Surprisingly, however, Cl2-exposed A. fumigatus challenged mice had a specific impairment in the production of IL-17A and IL-22 in the lungs compared with mice exposed to room air and challenged with A. fumigatus. In summary, our results indicate that Cl2 exposure markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.

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“…However, IL-17 has been associated with certain forms of severe asthma (34), CF (40), and chronic obstructive pulmonary disease (44), and in these chronic lung diseases IL-17 may contribute to pathology. The role of IL-22 and IL-22-binding protein in these diseases needs to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…In the gastrointestinal tract it has been shown that a critical source of IL-22 is innate lymphoid cells (ILC3 cells), but it remains unclear whether this population is important in the lung. Patients with cystic fibrosis (CF) have large numbers of IL-22 cells, and the vast majority of these cells at the time of lung transplantation are CD4 1 cells (40). In the setting of CF, these cells may be important in maintaining mucosal immunity against CF pathogens.…”

Section: Il-22 and Mucosal Immunitymentioning

confidence: 99%

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

Kolls

2014

Annals ATS

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The HIV epidemic has clearly demonstrated the critical role CD4 1 T cells play in preventing opportunistic infections in the lung. The types of CD4 1 effector T-cell populations in the lung have significantly expanded over the last 8-10 years with the discovery of helper T type 17 cells, and this review summarizes the field and discusses how these effector cells may be exploited to augment mucosal immunity in the lung.

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Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes

Cited by 66 publications

References 72 publications

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

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Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes

Cited by 66 publications

References 72 publications

Increased susceptibility of Cftr−/− mice to LPS-induced lung remodeling

Increased susceptibility of Cftr−/− mice to LPS-induced lung remodeling

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

Contact Info

Product

Resources

About

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling

Increased susceptibility of Cftr^−/− mice to LPS-induced lung remodeling