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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
NLRP12 modulates host defense through IL-17A-CXCL1 axis
S Cai1, S Batra1,2, F Del Piero1
1Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana, USA.
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.
Insights
NLRP12 is crucial for host defense against Klebsiella pneumoniae lung infections. It regulates immune cell activation, cytokine production, and neutrophil recruitment, ultimately impacting survival and bacterial clearance.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Klebsiella pneumoniae causes severe pulmonary infections.
- The role of NLRP12 (NOD-like receptor family pyrin domain containing 12) in K. pneumoniae infection is not well understood.
- NLRP12 is upregulated in human pneumonic lungs.
Purpose of the Study:
- To elucidate the function of NLRP12 in host defense against K. pneumoniae.
- To investigate the signaling pathways regulated by NLRP12 during K. pneumoniae infection.
Main Methods:
- Used NLRP12-silenced human macrophages and Nlrp12(-/-) murine macrophages.
- Infection models with Klebsiella pneumoniae.
- Assessed activation of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and histone deacetylases (HDACs).
- Measured interleukin-1β (IL-1β) production.
- Evaluated host survival, bacterial clearance, and neutrophil recruitment.
- Employed bone marrow chimeras and intratracheal administration of IL-17A+ CD4 T cells or CXCL1+ macrophages.
Main Results:
- NLRP12 deficiency reduced NF-κB and MAPK activation, and HDAC expression in response to K. pneumoniae.
- NLRP12 is essential for IL-1β production in macrophages.
- Host survival, bacterial clearance, and neutrophil recruitment are NLRP12-dependent.
- Hematopoietic cell-derived NLRP12 signaling is critical for host defense.
- IL-17A and CXCL1 pathways modulate host defense in NLRP12-deficient mice.
Conclusions:
- NLRP12 plays a vital role in innate and adaptive immunity against K. pneumoniae lung infections.
- The NLRP12-IL-17A-CXCL1 axis is critical for modulating neutrophil recruitment and host defense.
- Targeting NLRP12 may offer therapeutic strategies for K. pneumoniae-induced pneumonia.
