Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Siegmann, Nanna; Worbs, David; Effinger, Frauke; Bormann, Tobias; Gebhardt, M.; Ulrich, Martina; Wermeling, Fredrik; Müller-Hermelink, Eva; Biedermann, Tilo; Tighe, Mike; Edwards, Michael J.; Caldwell, Charles C.; Leadbetter, Elizabeth A.; Karlsson, Mikael C. I.; Becker, Katrin Anne; Gulbins, Erich; Döring, Gerd

doi:10.1159/000362984

Cited by 26 publications

(17 citation statements)

References 41 publications

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“…They can identify glycolipid antigens such as CDId, a highly conserved non-polymorphic MHC class I-like molecule. It has been shown by Seigmann et al [176] that CFTR deficiency in CF mouse models provokes a significant increase of iNKT cells in the lung. Thus, in CF lungs ceramide-mediated cell death results in activation of iNKT cells that drive the recruitment of inflammatory cells to the lung tissue, further promoting inflammation and lung tissue injury [176].…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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BackgroundThe airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics.DiscussionIn this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes.ConclusionCF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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“…Recently, it has become increasingly evident that B-cells are not only responders to T-cell help, but in exchange are important programmers of the CD4 T-cell response including priming and induction of T-cell memory 97 . In patients with CF, there is significant evidence supporting inefficient immune adaptive functions including effector functions of, NK cells 98 , B-cells 99 and T-cell abnormalities 86,100 ultimately also contributing to ineffective management of CF pathophysiology which is directed by downstream communication circuits related through MΦs and dendritic cells.…”

Section: The Cf Phagocyte and Adaptive Communicationmentioning

confidence: 99%

Cystic Fibrosis Lung Immunity: The Role of the Macrophage

2016

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Cystic fibrosis (CF) pathophysiology is hallmarked by excessive inflammation and the inability to efficiently resolve lung infections, contributing to major morbidity and eventually the mortality of patients with this disease. Macrophages (MΦs) are major players in lung homeostasis through their diverse contributions to both the innate and adaptive immune networks. The setting of MΦ function and activity in CF is multifaceted, encompassing the response to the unique environmental cues in the CF lung as well as the intrinsic changes resulting from CFTR dysfunction. The complexity is further enhanced with the identification of modifier genes, which modulate the CFTR contribution to disease, resulting in epigenetic and transcriptional shifts in MΦ phenotype. This review focuses on the contribution of MΦ to lung homeostasis, providing an overview of the diverse literature and various perspectives on the role of these immune guardians in CF.

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“…Acid-SMase-mediated production of ceramide has been implicated in promoting pulmonary inflammation by recruiting activated neutrophils, and increasing susceptibility of bacterial infection (Becker et al, 2010). The pathology related to neutrophil inflammation is ameliorated in humans using a pharmacological inhibitor of acid-SMase or in the Cftr −/− / Smdp1 −/− mouse model (Siegmann et al, 2014; Teichgraber et al, 2008). Acid-SMase-induction of ceramide not only targets epithelial cell apoptosis in the early phase of cystic fibrosis, it also plays an important role in the high susceptibility of Pseudomonas aeruginosa infection.…”

Section: Sphingolipids In Neutrophil Regulationmentioning

confidence: 99%

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Espaillat

Kew

Obeid

2017

Advances in Biological Regulation

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Bioactive sphingolipids are regulators of immune cell function and play critical roles in inflammatory conditions including ulcerative colitis. As one of the major forms of inflammatory bowel disease, ulcerative colitis pathophysiology is characterized by an aberrant intestinal inflammatory response that persists causing chronic inflammation and tissue injury. Innate immune cells play an integral role in normal intestinal homeostasis but their dysregulation is thought to contribute to the pathogenesis of ulcerative colitis. In particular, neutrophils are key effector cells and are first line defenders against invading pathogens. While the activity of neutrophils in the intestinal mucosa is required for homeostasis, regulatory mechanisms are equally important to prevent unnecessary activation. In ulcerative colitis, unregulated neutrophil inflammatory mechanisms promote tissue injury and loss of homeostasis. Aberrant neutrophil function represents an early checkpoint in the detrimental cycle of chronic intestinal inflammation; thus, dissecting the mechanisms by which these cells are regulated both before and during disease is essential for understanding the pathogenesis of ulcerative colitis. We present an analysis of the role of sphingolipids in the regulation of neutrophil function and the implication of this relationship in ulcerative colitis.

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Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Cited by 26 publications

References 41 publications

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Cystic Fibrosis Lung Immunity: The Role of the Macrophage

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

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