ABSTRACT
Alveolar macrophages (AMs) are pivotal for maintaining lung immune homeostasis. We demonstrated that deletion of liver kinase b1 (Lkb1) in CD11c+ cells led to greatly reduced AM abundance in the lung due to the impaired self-renewal of AMs but not the impeded pre-AM differentiation. Mice with Lkb1-deficient AMs exhibited deteriorated diseases during airway Staphylococcus aureus (S. aureus) infection and allergic inflammation, with excessive accumulation of neutrophils and more severe lung pathology. Drug-mediated AM depletion experiments in wild type mice indicated a cause for AM reduction in aggravated diseases in Lkb1 conditional knockout mice. Transcriptomic sequencing also revealed that Lkb1 inhibited proinflammatory pathways, including IL-17 signaling and neutrophil migration, which might also contribute to the protective function of Lkb1 in AMs. We thus identified Lkb1 as a pivotal regulator that maintains the self-renewal and immune function of AMs.
Subject(s)
Asthma/enzymology , Cell Self Renewal , Lung/enzymology , Macrophages, Alveolar/enzymology , Pneumonia, Bacterial/enzymology , Protein Serine-Threonine Kinases/metabolism , Staphylococcal Infections/enzymology , AMP-Activated Protein Kinases , Animals , Asthma/genetics , Asthma/immunology , CD11 Antigens/genetics , CD11 Antigens/metabolism , Disease Models, Animal , Homeostasis , Interleukin-17/genetics , Interleukin-17/metabolism , Lung/immunology , Lung/microbiology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/microbiology , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration , Pneumonia, Bacterial/genetics , Pneumonia, Bacterial/immunology , Pneumonia, Bacterial/microbiology , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Staphylococcal Infections/genetics , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , TranscriptomeABSTRACT
OBJECTIVE: To investigate the effects of human amniotic mesenchymal stem cellï¼AMSCï¼ on acute graft-versus-host disease (aGVHD) in xenotransplatation. METHODS: NPG mice were injected with human PBMNC via tail vein to establish a xenografted aGVHD model. The mice in the experimental group were divided into PBMNC infusion group and PBMNC+AMSC co-infusion group, the general condition, survival time and manifestations of aGVHD were observed, the body weight and blood routine indicators were detected, the pathological changes of aGVHD target organs (lung, liver, spleen, small intestine) were observed by HE staining, and the levels of human T cells in peripheral blood, tissues and organs of mice was detected by flow cytometry. RESULTS: The manifestations of aGVHD (lassitude hunchback, shrub, weight reduction, etc.) and the pathological damage of the target organs (lung, liver, spleen, intestine) in PBMNC+AMSC co-infusion group were lighter than those in PBMNC infusion group. Moreover, the PBMNC and AMSC co-infusion significantly reduced the implantion proportion of human T lymphocytes (CD3+, CD45+) in mice and increased the ratio of CD4+/CD8+. CONCLUSION: Infusion of human-derived AMSC can attenuate the manifestations of aGVHD in mouse xenografts to a certain level, and improve the pathological damage of receptor target organs.
Subject(s)
Graft vs Host Disease , Mesenchymal Stem Cells , Acute Disease , Animals , Heterografts , Humans , Mice , T-Lymphocytes , Transplantation, HeterologousABSTRACT
Alveolar macrophages (AMs) are pivotal for maintaining the lung homeostasis, but how the development and function of AMs regulated remains largely unknown. In the present study, we demonstrated that the number of AMs was controlled by the Tsc1 protein. Cd11c-specific deletion of Tsc1 caused inefficient transition from pre-AMs to AMs in lung, which led to a great reduction of AM population. Ablation of Tsc1 downregulated the expression of surface marker CD64 and SiglecF on AMs. We further showed that conditional knockout of Tsc1 led to enhanced proliferation and increased reactive oxygen species (ROS) production and phagocytosis in AMs. These results indicated that Tsc1 was a critical regulator of development, proliferation and function in AMs.
