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Research: Novel NLR Proteins and Their Functions in Immune Privilige and Tolerance
The human Nod-like Receptor (NLR) family has been discovered within the last decade and studies on its 23 members have been rapidly accumulating. Among the members with defined functions NOD1 and NOD2 have been shown to detect bacteria specific macromolecular components, namely parts of peptidoglycan, once they have reached the cytoplasm. Upon recognition of pathogen associated molecules the NODs activate the innate immune signaling pathways via NF-kB. Mutations in the NOD2 gene have been correlated with Crohn’s disease, the symptoms of which include abdominal and intestinal inflammation and pain. Mutations in another important family member Cryopyrin/NLRP3 have been linked to the autoinflammatory diseases Muckle-Wells, NOMID/ CINCA (Neonatal Onset Multisystem Inflammatory Disease) and FCU (Familial Cold Urticaria). The function of NLRP3 proteins was found to be the assembly of the the cytoplasmic multi-protein complexes known as inflammasomes, consistent of the adapter ASC and caspase 1 and/or 5, which in turn become enzymatically active. The assembly of the NLRP3 inflammasome is triggered by certain bacterial and viral molecules (RNA, DNA, peptidoglycan and others) as well as cellular and tissue damage associated stimulants (such as ATP, monosodium urate and cholesterol crystals), which accumulate in the extracellular fluid upon damage. Active caspases 1 and/or 5 are known to cleave pro-interleukins IL-1b, IL-18 and IL-33 to their mature form, which after secretion initiate innate immune signaling. Together with the other pro-inflammatory cytokines, such as TNFa and IL-6, upregulated via the NLR- or TLR (Toll-like Receptor)-instigated NF-kB signaling, they induce local edema formation, trigger the systemic inflammation and fever responses and in the long run activate the adaptive immune system, at the end resulting in the elimination of the pathogenic bacteria, viruses or other dangerous agents from the body.
Aside from the NLR members proficient in the induction of inflammation, a subgroup with anti-inflammatory properties has become recognizable. For example, NLRP10 and NLRP12 have been shown to downregulate NF-kB activity and caspase 1 cleavage, respectively. Two papers suggested that NLRP7 may belong to this anti-inflammatory subgroup. We plan to determine the effects the novel NLR family members NLRP7, NLRP13 and NLRC3 have on inflammation induction or suppression, in broader terms to find their place in the immune system. The expression of NLRP7 and NLRP13 genes is restricted to the placenta and testes, among the most important sites of immune privilege. The mechanisms of the immune tolerance induced by the developing fetus is a subject of intense study with many open questions to answer.
The initial steps of our project will be bioinformatic analyses on the genomic structures of NLRP7, NLRP13 and NLRC3 followed by meta analyses of the expression patterns of the gene in the freely available microarray databases. These studies will give us clues as to which pathways to focus on. Using the NLRP7, NLRP13 and NLRC3 polyclonal and monoclonal antibodies that will be developed, we will carry out immunoprecipitation experiments and determine probable protein interaction partners via mass spectrometry. We will perform detailed experiments on proteins with anti-inflammatory properties and any interactions will be confirmed. We will study the ability of NLRP7, NLRP13 and NLRC3 to affect the NF-kB pathway via luciferase assays, and caspase-1 activation, via ELISA for IL-1b secretion, in overexpression conditions.
The results of our studies will contribute not only to the clarification of the placental immune privilege but bear the potential to shed light on the tolerance induced by established tumors.
Seminar at Osaka University, 19.02.2009
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