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Mota, Ryerson Fonseca ; de Araujo, Paulo Henrique Cavalcanti ; Cezine, Maria Eduarda Ramos ; Matsuo, Flavia Sayuri ; Metzner, Rodrigo Jair Morandi ; de Biagi Junior, Carlos Alberto Oliveira ; Peronni, Kamila Chagas ; Hayashi, Hiroki ; Shimamura, Munehisa ; Nakagami, Hironori ; Osako, Mariana Kiomy

• Tipo de documento: Artigo Científico
• Fonte: BIOMED RESEARCH INTERNATIONAL; v. 2022, p. 13-pg., 2022-04-12.

Resumo

High serum levels of osteoprotegerin (OPG) are found in patients with obesity, type 2 diabetes, sepsis, or septic shock and are associated with a high mortality rate in stroke. The primary known function of OPG is to bind to the receptor activator of NF-kappa B ligand (RANKL), and by doing so, it inhibits the binding between RANKL and its receptor (RANK). TLR4 signaling in macrophages involves TRAF6 recruitment and contributes to low-grade chronic inflammation in adipose tissue. LPS is a classical activator of the TLR4 pathway and induces the expression of inflammatory cytokines in macrophages. We have previously observed that in the presence of RANKL, there is no LPS-induced activation of TLR4 in macrophages. In this study, we investigated the crosstalk between RANK and TLR4 pathways in macrophages stimulated with both RANKL and LPS to unveil the role of OPG in inflammatory processes. We found that RANKL inhibits TLR4 activation by binding to RANK, promoting the binding between TRAF6 and RANK, lowering TLR4 activation and the expression of proinflammatory mediators. Furthermore, high OPG levels aggravate inflammation by inhibiting RANKL. Our findings elect RANKL as a candidate for drug development as a way to mitigate the impact of obesity-induced inflammation in patients. (AU)

• Processo FAPESP: 16/22009-8 - Sistema RANKL e a Ativação Metabólica de Macrófagos na Inflamação do Tecido Adiposo
• Beneficiário: Rodrigo Jair Morandi Metzner
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/00508-2 - Sistema RANKL na via de sinalização TLR4
• Beneficiário: Ryerson Fonseca Mota
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 14/11092-6 - Sistema RANKL na regulação de macrófagos presentes na inflamação do tecido adiposo
• Beneficiário: Mariana Kiomy Osako
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 16/00651-0 - Sistema RANKL na polarização M1/M2 de macrófagos
• Beneficiário: Paulo Henrique Cavalcanti de Araújo
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 15/26088-7 - Estudo da via de sinalização RANKL/RANK/OPG na diferenciação do tecido adiposo bege
• Beneficiário: Flávia Sayuri Matsuo
• Modalidade de apoio: Bolsas no Brasil - Doutorado