Bone Marrow Transplantation Rescues Monocyte Recruitment Defect and Improves Cystic Fibrosis in Mice.
Zhichao FanElise PitmonLai WenJacqueline MillerErik EhingerRana HerroWei LiuJu ChenZbigniew MikulskiDouglas J ConradAlex MarkiMarco OrecchioniPuja KumariYanfang Peipei ZhuPaola M MarcovecchioCatherine C HedrickCraig A HodgesVijay A RathinamKepeng WangKlaus LeyPublished in: Journal of immunology (Baltimore, Md. : 1950) (2022)
Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multiorgan inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. CFTR functions in epithelial cells have traditionally been thought to cause the disease symptoms. Recent work has shown an additional defect: monocytes from CF patients show a deficiency in integrin activation and adhesion. Because monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTR ΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type (WT) bone marrow after sublethal irradiation replaced most (60-80%) CF monocytes with WT monocytes, significantly improved survival, and reduced inflammation. WT/CF mixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. WT mice reconstituted with CF bone marrow also show lethality, suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease. We also show that monocyte-specific knockout of CFTR retards weight gains and exacerbates dextran sulfate sodium-induced colitis. Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients.
Keyphrases
- cystic fibrosis
- bone marrow
- pseudomonas aeruginosa
- dendritic cells
- lung function
- wild type
- end stage renal disease
- peripheral blood
- mesenchymal stem cells
- chronic kidney disease
- high fat diet induced
- ejection fraction
- newly diagnosed
- oxidative stress
- biofilm formation
- peritoneal dialysis
- prognostic factors
- immune response
- adipose tissue
- transcription factor
- insulin resistance
- physical activity
- stem cells
- type diabetes
- endothelial cells
- escherichia coli
- coronary artery disease
- staphylococcus aureus
- radiation therapy
- cardiovascular events
- patient reported
- dna methylation
- candida albicans
- skeletal muscle
- soft tissue