Role of innate immunity and systemic inflammation in cystic fibrosis disease progression

Abstract

Pathophysiological manifestations of cystic fibrosis (CF) result from a functional defect in the cystic fibrosis transmembrane conductance regulator (CFTR) paving way for mucus obstruction and pathogen colonization. The role of CFTR in modulating immune cell function and vascular integrity, irrespective of mucus thickening, in determining the host cell response to pathogens/allergens and causing systemic inflammation is least appreciated. Since CFTR plays a key role in the conductance of anions like Cl^-, loss of CFTR function could affect various basic cellular processes, such as cellular homeostasis, lysosome acidification, and redox balance. CFTR aids in endotoxin tolerance by regulating Toll-like receptor-mediated signaling resulting in uncontrolled activation of innate immune cells. Although leukocytes of CF patients are hyperactivated, they exhibit compromised phagosome activity thus favouring the orchestration of sepsis from defective pathogen clearance. This review will emphasize the importance of innate immunity and systemic inflammatory response in the development of CF and other CFTR-associated pathologies.

Keywords: Cystic fibrosis; Innate immunity; NETosis; PRR-Mediated signaling; Systemic inflammation; T1/T2 immune cell ratio.

Fig. 1

Altered mucin unfolding and mucus formation from secretory cells in CF. In normal conditions, CFTR-mediated regulation of Cl⁻ conductance and ENaC suppression facilitates even distribution of Na⁺ and water molecules across the lumen, forming the basis for proper mucin unfolding and spreading. In CF, ENaC is activated leading to inadequate levels of Na⁺ in the extracellular space resulting in altered mucin unfolding, wherein the absence of water molecules from ENaC activation and aquaporin suppression stifle the hydration of heavily glycosylated mucins to result in improper spreading and hypercondensation. Also, loss of mucociliary action results in the accumulation and thickening of mucus.

Fig. 2

Pathophysiological effects of dysfunctional CFTR at cellular level. CFTR-induced physiological changes common to all cell types (including leukocytes, 2A), and those specific for epithelial and endothelial cells (2B) are shown. Phosphatase and tensin homologue (PTEN) associates with CFTR to suppress TLR4/NF-κB signaling and inflammosome activation. CFTR regulates Cl⁻ levels in the lumen of lysosomes to establish an acidic environment and produce HOCl upon NOX2 activation for effective oxidative burst. CFTR also facilitates endotoxin tolerance, ciliary movement, and epithelial barrier maintenance through its interaction with Src kinase, ZO-1, and Ezrin. In CFTR dysfunction, compromised lysosomal acidification results in reduced pathogen clearance and impaired autophagy. Further, loss of epithelial barrier function obliterates endotoxin tolerance in epithelial cells, where microbial breach of the epithelial barrier orchestrates elevated PRR-mediated signaling followed by leukocyte infiltration in the parenchyma or even sepsis when microbes enter the circulation.

Fig. 3

Pathophysiological manifestation of CF in the lungs. In normal lungs, mucociliary clearance ensures that no microbes are hoarding the airways. In CF lungs, loss of airway surface liquid, defective mucin unfolding, mucus condensation, and loss of mucociliary activity contribute to accumulation of mucus within the airways thus favouring colonization of microbes, with infiltration of leukocytes and heightened NETosis contributing to tissue destruction and fibrosis.

Fig. 4

Pathophysiological manifestations of CF in the gut, pancreas, and liver. Under normal conditions, gut microbiome is maintained within the outer mucosal layer whereas in CF, they breach into the leaky epithelium and stir an innate immune response involving NETosis that could influence liver physiology by transfer of DAMPs, microbes, and PAMPs into the hepatic portal system. Also, obstruction of the bile duct by gall stones further aggravates liver cirrhosis, while obstruction of the pancreatic duct or common bile/pancreatic duct by the mucus plug results in pancreatitis.

Fig. 5

T1/T2 immune cell ratio switching in circulation and parenchyma of organs in CF. Due to elevated PAMP response and the release of proinflammatory cytokines in CF, innate immune cell hyperactivation in blood occurs where the infiltrated monocytes, neutrophils, and CD4⁺ T cells become polarized into proinflammatory type 1 immune cells (M1 macrophage/NETosing neutrophil/Th1 cells) leading to decreased T1/T2 immune cell ratio within parenchyma. This switch in ratio culminates in the release of more proinflammatory cytokines into the circulation to accelerate the systemic inflammatory response.