Critical Role of TLR2 and MyD88 for Functional Response of Macrophages to a Group IIA-Secreted Phospholipase A(2) from Snake Venom

Autor(es)

Leiguez, Elbio ^[1] ; Giannotti, Karina Cristina ^[1] ; Moreira, Vanessa ^[1] ; Matsubara, Marcio Hideki ^[1] ; Maria Gutierrez, Jose ^[2] ; Lomonte, Bruno ^[2] ; Pablo Rodriguez, Juan ^{[3, 4]} ; Balsinde, Jesus ^[4] ; Teixeira, Catarina ^[1]

Afiliação do(s) autor(es)

^[1] Inst Butantan, Farmacol Lab, Sao Paulo - Brazil

^[2] Univ Costa Rica, Fac Microbiol, Inst Clodomiro Picado, San Jose - Costa Rica

^[3] Univ Nacl Nordeste, FACENA, Lab Invest Prot, Corrientes - Argentina

^[4] Inst Biol & Genet Mol, Eicosanoid Res Div, Valladolid - Spain

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 9, n. 4 APR 9 2014.
• Citações Web of Science: 5

Resumo

The snake venom MT-III is a group IIA secreted phospholipase A(2) (sPLA(2)) enzyme with functional and structural similarities with mammalian pro-inflammatory sPLA(2)s of the same group. Previously, we demonstrated that MT-III directly activates the innate inflammatory response of macrophages, including release of inflammatory mediators and formation of lipid droplets (LDs). However, the mechanisms coordinating these processes remain unclear. In the present study, by using TLR2(-/-) or MyD88(-/-) or C57BL/6 (WT) male mice, we report that TLR2 and MyD88 signaling have a critical role in MT-III-induced inflammatory response in macrophages. MT-III caused a marked release of PGE(2), PGD(2), PGJ(2), IL-1 beta and IL-10 and increased the number of LDs in WT macrophages. In MT-III-stimulated TLR2(-/-) macrophages, formation of LDs and release of eicosanoids and cytokines were abrogated. In MyD88(-/-) macrophages, MT-III-induced release of PGE(2), IL-1 beta and IL-10 was abrogated, but release of PGD(2) and PGJ(2) was maintained. In addition, COX-2 protein expression seen in MT-III-stimulated WT macrophages was abolished in both TLR2(-/-) and MyD88(-/-) cells, while perilipin 2 expression was abolished only in MyD88 2/2 cells. We further demonstrated a reduction of saturated, monounsaturated and polyunsaturated fatty acids and a release of the TLR2 agonists palmitic and oleic acid from MT-III-stimulated WT macrophages compared with WT control cells, thus suggesting these fatty acids as major messengers for MT-III-induced engagement of TLR2/MyD88 signaling. Collectively, our findings identify for the first time a TLR2 and MyD88-dependent mechanism that underlies group IIA sPLA(2)-induced inflammatory response in macrophages. (AU)

• Processo FAPESP: 11/21341-5 - Estudo de mecanismos envolvidos na formação de corpúsculos lipídicos induzidos por uma fosfolipase A2 isolada do veneno da serpente Bothrops asper em macrófagos isolados: participação de fatores da homeostasia lipídica
• Beneficiário: Catarina de Fatima Pereira Teixeira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/06345-1 - Estudo dos fatores envolvidos na formação de corpúsculos lipídicos, induzidos por uma Fosfolipase A2, isolada do veneno de serpente: síntese e metabolismo de lipídios
• Beneficiário: Elbio Leiguez Junior
• Modalidade de apoio: Bolsas no Brasil - Doutorado