Abstract
The majority of nucleotide binding domain leucine rich repeats-containing (NLR) family members has yet to be functionally characterized. Of the described NLRs, most are considered to be proinflammatory and facilitate IL-1β production. However, a newly defined sub-group of NLRs that function as negative regulators of inflammation have been identified based on their abilities to attenuate NF-κB signaling. NLRP12 (Monarch-1) is a prototypical member of this sub-group that negatively regulates both canonical and noncanonical NF-κB signaling in biochemical assays and in colitis and colon cancer models. The role of NLRP12 in infectious diseases has not been extensively studied. Here, we characterized the innate immune response of Nlrp12−/− mice following airway exposure to LPS, Klebsiella pneumoniae and Mycobacterium tuberculosis. In response to E. coli LPS, Nlrp12−/− mice showed a slight decrease in IL-1β and increase in IL-6 production, but these levels were not statistically significant. During K. pneumoniae infection, we observed subtle differences in cytokine levels and significantly reduced numbers of monocytes and lymphocytes in Nlrp12−/− mice. However, the physiological relevance of these findings is unclear as no overt differences in the development of lung disease were observed in the Nlrp12−/− mice. Likewise, Nlrp12−/− mice demonstrated pathologies similar to those observed in the wild type mice following M. tuberculosis infection. Together, these data suggest that NLRP12 does not significantly contribute to the in vivo host innate immune response to LPS stimulation, Klebsiella pneumonia infection or Mycobacterium tuberculosis.
Highlights
Initiation and termination of the host innate immune response to pathogenic bacteria infection is tightly regulated
To evaluate cytokine production in response to pathogen stimulation, dendritic cells were isolated from the bone marrow, cultured and matured as previously described [14]. These primary cells were stimulated with pathogen associated molecular patterns (PAMPs) associated with E. coli, K. pneumoniae and M. tuberculosis infection
TNFa levels were significantly increased in Nlrp122/2 dendritic cell cultures following stimulation with E. coli derived LPS, K. pneumoniae derived LPS and the M. tuberculosis PAMP TDB (Figure 1B)
Summary
Initiation and termination of the host innate immune response to pathogenic bacteria infection is tightly regulated. The host response to respiratory bacteria is initially driven through the stimulation of TLRs. TLR activation signals through the NF-kB pathway to up-regulate the transcription of proinflammatory cytokines, including IL-1b, TNFa, and IL-6, which are essential for the recruitment of leukocytes to the lung and clearance of the infection. TLR activation signals through the NF-kB pathway to up-regulate the transcription of proinflammatory cytokines, including IL-1b, TNFa, and IL-6, which are essential for the recruitment of leukocytes to the lung and clearance of the infection Mice deficient in these three proinflammatory cytokines have demonstrated significant increases in morbidity and mortality during respiratory infections with Klebsiella pneumoniae and Mycobacterium tuberculosis [1,2]. An inflammasome forms following the activation of a particular NLR by a specific danger signal, which results in the activation of caspase-1 and the subsequent posttranslational cleavage of pro-IL-1b and pro-IL-18 into their active forms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
