Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

Abstract

Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. The inflammatory response in CF is dominated by the activation of the innate immune system. Bacteria and fungi represent the key pathogens chronically colonizing the CF airways. In response, innate immune pattern recognition receptors, expressed by airway epithelial and myeloid cells, sense the microbial threat and release chemoattractants to recruit large numbers of neutrophils into CF airways. However, neutrophils fail to efficiently clear the invading pathogens, but instead release harmful proteases and oxidants and finally cause tissue injury. Here, we summarize and discuss current concepts and controversies in the field of innate immunity in CF lung disease, facing the ongoing questions of whether inflammation is good or bad in CF and how innate immune mechanisms could be harnessed therapeutically.

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

“…In particular, recent studies showed that upon recruitment into CF airways neutrophils undergo significant activation of both cAMP response element-binding protein (CREB) and mechanistic (formerly mammalian) target of rapamycin (mTOR) pathways, linked to surface upregulation of functional receptors (e.g., the receptor for advanced glycation end products) and metabolite transporters (e.g., glucose and amino acid transporters Glut1 and ASCT2) [43–45]. Since CF airways are enriched in inflammatory mediators and nutrients such as glucose and amino acids, these results suggest the ability of neutrophils to adapt to specific microenvironments through coordinated stress responses and metabolic reprogramming [reviewed in 46, 47]. …”

“…This process, well recognized in airway diseases such as CF and COPD, induces an upregulation of characteristic markers for secondary and primary granules (CD66b and CD63, respectively) on the surface of airway neutrophils and results in high oxidative and proteolytic activities. The latter was shown to be responsible for the cleavage as key receptors involved in neutrophil antibacterial activities such as CXCR1, CD16, and CD14 [43, 46–48]. Further studies revealed a role for airway neutrophils in regulation of the adaptive immune system, further emphasizing the multidimensional importance of neutrophil plasticity [37].…”

“…Temporally, innate immune effector responses are mostly protective in the initial phase of infection and inflammation, but they can become harmful and induce autoinflammatory complications if they fail to resolve, as exemplified in chronic lung diseases such as CF, IPF, and COPD [42]. From a cellular perspective, pulmonary innate immune cells can be further subdivided into 2 simplified categories: first, granulocytes (neutrophils, eosinophils, and basophils) that are short-lived and bear a higher acute pathogenic potential by rapidly releasing their toxic and tissue-damaging components (proteases and oxidants) upon local activation in airways [8, 46], and, second, mononuclear cells (monocytes, alveolar/interstitial macrophages, and dendritic cells) that are generally longer lived and more controlled in terms of enzyme and mediator release, mainly serving as antigen-presenting cells and scavengers of apoptotic bodies/debris and invading microbes. Short-lived innate immune cells play a major role in the early phase of acute respiratory conditions, such as neutrophils in lung infections or acute respiratory distress syndrome, whereas long-lived innate immune cells, such as macrophages and ILC, orchestrate chronic outcomes of tissue inflammation and remodeling in chronic pulmonary conditions like lung fibrosis/IPF and COPD.…”

Surfing motility is a complex adaptation dependent on the stringent stress response in Pseudomonas aeruginosa LESB58

“…The CF lung is considered a stressful environment due to increased oxidative stress levels [19], chronic activation of the innate immune system [20], and bacterial competition upon antibiotic exposure [12]. Therefore, here we aimed to characterize the role of the stringent stress response in relation to motility of the hypervirulent CF epidemic isolate LESB58.…”

Innate Immunity in Cystic Fibrosis: Novel Pieces of the Puzzle

“…First, Ralhan et al [5 ]provide a comprehensive overview covering and discussing several key players in the innate immune response in the context of the CF lung, i.e. airway epithelial cells, CF characteristic pathogens (focus: bacteria and fungi) and microbial pattern recognition receptors (e.g.…”