Abstract
We used an extracellular pathogen Klebsiella pneumoniae to determine the role of NLRP12 (NOD-like receptor (NLR) family pyrin domain containing 12) as this bacterium is associated with devastating pulmonary infections. We found that human myeloid cells (neutrophils and macrophages) and non-myeloid cells (epithelial cells) show upregulation of NLRP12 in human pneumonic lungs. NLRP12-silenced human macrophages and murine Nlrp12(-/-) macrophages displayed reduced activation of nuclear factor-κB and mitogen-activated protein kinase, as well as expression of histone deacetylases following K. pneumoniae infection. NLRP12 is important for the production of interleukin-1β (IL-1β) in human and murine macrophages following K. pneumoniae infection. Furthermore, host survival, bacterial clearance, and neutrophil recruitment are dependent on NLRP12 following K. pneumoniae infection. Using bone marrow chimeras, we showed that hematopoietic cell-driven NLRP12 signaling predominantly contributes to host defense against K. pneumoniae. Intratracheal administration of either IL-17A+ CD4 T cells or chemokine (C-X-C motif) ligand 1 (CXCL1+) macrophages rescues host survival, bacterial clearance, and neutrophil recruitment in Nlrp12(-/-) mice following K. pneumoniae infection. These novel findings reveal the critical role of NLRP12-IL-17A-CXCL1 axis in host defense by modulating neutrophil recruitment against this extracellular pathogen.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Marrow / immunology
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Bone Marrow / microbiology
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Bone Marrow / pathology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / microbiology
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CD4-Positive T-Lymphocytes / pathology
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CD4-Positive T-Lymphocytes / transplantation
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Chemokine CXCL1 / genetics
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Chemokine CXCL1 / immunology*
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Epithelial Cells / immunology
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Epithelial Cells / microbiology
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation
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Humans
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Klebsiella Infections / genetics
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Klebsiella Infections / immunology*
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Klebsiella Infections / microbiology
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Klebsiella Infections / pathology
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Klebsiella pneumoniae / immunology
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Lung / immunology
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Lung / microbiology
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Lung / pathology
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Macrophages / immunology*
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Macrophages / microbiology
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Macrophages / pathology
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Macrophages / transplantation
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophil Infiltration
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Neutrophils / immunology
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Neutrophils / microbiology
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Neutrophils / pathology
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Pneumonia / genetics
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Pneumonia / immunology*
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Pneumonia / microbiology
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Pneumonia / pathology
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Signal Transduction
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Transplantation Chimera
Substances
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Chemokine CXCL1
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Cxcl1 protein, mouse
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Interleukin-17
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Intracellular Signaling Peptides and Proteins
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NLRP12 protein, mouse