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NLRC4 inflammasome and the immune response and bone resorption in experimental periodontal disease

Grant number: 14/17544-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): November 01, 2014
Effective date (End): October 31, 2015
Field of knowledge:Health Sciences - Dentistry - Periodontology
Principal Investigator:Carlos Rossa Junior
Grantee:Fernanda Regina Godoy Rocha
Supervisor abroad: Shannon Wallet
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : University of Florida, Gainesville (UF), United States  
Associated to the scholarship:14/04926-8 - NLRC4 and NLRP3 inflammasomes in experimental periodontal disease induced by Aggregatibacter actinomycetemcomitans, BP.DR


Periodontal disease is the most prevalent lytic disease of bone in humans. It is initiated and maintained by microorganisms in the dental biofilm, but most of the tissue damage is mediated by the immune response to these microorganisms. It is thus, a good study model for host-microbial interactions and the information generated from these models can be useful for various conditions of infectious origin and also conditions characterized by a chronic inflammatory response. Inflammasomes are multi-protein complexes that include a nucleotide-oligomerization domain leucine-rich repeat containing receptor (NLR), caspase-1 and an adaptor protein. These complexes participate in the sensing of microbial (MAMPs) and tissue damage (DAMPs)-derived molecular patterns by the innate immunity. Caspase-1 is the central effector molecule in these protein complexes and participates in the processing of inflammatory cytokines and apoptosis. NLRC4 (Ipaf) inflammasome is expressed in myeloid cells and participates in the immune response to Gram-negative bacteria presenting a type III or IV secretory system; but its role on the bone resorption associated with periodontal infection has not been investigated. Our hypothesis is that the NLRC4 inflammasome has an important role in the immune response associated with destructive periodontal disease and affects alveolar bone resorption. Preliminary experiments demonstrate a marked reduction of the alveolar bone resorption induced by bacterial LPS in NLRC4 and Caspase-1 KO knockout mice. The fact that NLRC4 KO mice also showed reduced bone loss indicate that this inflammasome have a important role in the immune response in periodontal tissues that is not redundant with that of other caspase-1 activating inflammasomes, such as NLRP1 and NLRP3. T-cell mediated inhibition of inflammasomes has been recently described as an endogenous control of the activation of innate immune cells, demonstrating the reciprocal regulation between the innate and adaptive arms of the host response. This inhibition of NLRP1 and NLRP3 inflammasomes involves not only Treg but also other subtypes of CD4+ T cells and particularly TNF-family genes, such as TNF-alpha and RANKL. Interestingly, activated CD4+ T cells were not able to inhibit the activity of NLRC4 inflammasome in macrophages. A better understanding of the role played by the different inflammasomes in various disease models as well as of the molecular mechanisms of inflammasome inhibition can provide novel opportunities for immune modulation therapies. To determine the role of NLRC4 in periodontal disease and test our main hypothesis we propose the following specific aims:1. Determine the role of NLRC4 on the immune response in experimental periodontal diseaseWe will use mice genetically 'normal' (wild-type, WT) and mice deficient (knockout, KO) for NLRC4 and Caspase-1 and induce periodontal disease by injecting heat-killed Aggregatibacter actinomycetemcomitans into the palatal gingival tissues adjacent to the upper first molars. Immune response will be characterized by analyzing the lymph nodes draining the oral cavity by flow cytometry and also by determination of production of inflammatory cytokines in the diseased gingival tissues using multi-ligand ELISAs. Descriptive, stereometric and immunohistochemistry analysis will also be used to study the inflammatory response in the periodontal microenvironment;2. Assess the role of NLRC4 inflammasome on osteoclastogenesis and osteoblast apoptosis/differentiationOsteoclast precursor cells (bone marrow-derived macrophages) and pan-T cells will be obtained from WT, NLRC4 and Caspase-1 KO mice and osteoclast differentiation will be induced by either RANKL (precursor cells only) or bacterial LPS (co-cultures). Primary osteoblast cells obtained from these animals will be exposed to apoptotic stimuli and differentiation stimuli. The outcomes of interest will be number and activity of osteoclasts. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ROCHA, FERNANDA R. G.; DELITTO, ANDREA E.; CHAVES DE SOUZA, JOAO A.; MALDONADO, LAURA A. G.; WALLET, SHANNON M.; ROSSA JR, CARLOS. NLRC4 inflammasome has a protective role on inflammatory bone resorption in a murine model of periodontal disease. Immunobiology, v. 225, n. 1 JAN 2020. Web of Science Citations: 0.

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