Natural killer cell effector function is critical for host defense against alcohol-associated bacterial pneumonia
Year: 2024
Type: article
Abstract: Alcohol use is an independent risk factor for the development of bacterial pneumonia due, in part, to impaired mucus-facilitated clearance, macrophage phagocytosis, and recruitment of neutrophils. Alcohol consumption is also known to reduce peripheral natural killer (NK) cell numbers and compromise NK cell cytolytic activity, especially NK cells with a mature phenotype. However, the role of innate lymphocytes, such as NK cells during host defense against alcohol-associated bacterial pneumonia is essentially unknown. We have previously shown that indole supplementation mitigates increases in pulmonary bacterial burden and improves pulmonary NK cell recruitment in alcohol-fed mice, which were dependent on aryl hydrocarbon receptor (AhR) signaling. Employing a binge-on-chronic alcohol-feeding model we sought to define the role and interaction of indole and NK cells during pulmonary host defense against alcohol-associated pneumonia. We demonstrate that alcohol dysregulates NK cell effector function and pulmonary recruitment via alterations in two key signaling pathways. We found that alcohol increases transforming growth factor beta (TGF-β) signaling while suppressing AhR signaling. We further demonstrated that NK cells isolated from alcohol-fed mice have a reduced ability to kill Klebsiella pneumoniae. NK cell migratory capacity to chemokines was also significantly altered by alcohol, as NK cells isolated from alcohol-fed mice exhibited preferential migration in response to CXCR3 chemokines but exhibited reduced migration in response to CCR2, CXCR4, and CX3CR1 chemokines. Together this data suggests that alcohol disrupts NK cell-specific TGF-β and AhR signaling pathways leading to decreased pulmonary recruitment and cytolytic activity thereby increasing susceptibility to alcohol-associated bacterial pneumonia.
Source: npj Biofilms and Microbiomes
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,990
Awards: Mechanisms by Which Alcohol-Induced Dysbiosis Impairs Host Defense Against Klebsiella Pneumoniae, G1600607514, G2378195067, G2782907130, G3511436077, G3869033735, G4245024374, Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia, G6487643833, G6892915839, G7196223058, G7612851281, Gut bacterial metallophores in the development and severity of inflammatory bowel disease, G889299280, G9000110408, Alcohol Center Of Research -- Nebraska (ACORN), Summer Undergraduate Alcohol Research Program, The role of alcohol-associated microbiota membrane vesicles in mucosal immunity, CoPARC: Colorado Pulmonary-Alcohol Research Collaborative
OpenAlex ID: W4402166780