Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice

Abstract

Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na+/K+-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate receptors by acting on two different receptors (tumor necrosis factor receptor 1 [TNFR1] and TNFR2) that have distinct functions and expression. The activation of constitutively and ubiquitously expressed TNFR1 leads to the expression of pro-inflammatory cytokines. Thus, this study aimed to elucidate the effects of ouabain in a TNFR1 knockout (KO) mouse model. Interestingly, the hippocampus of TNFR1 KO mice showed a basal increase in both TNFR2 membrane expression and brain-derived neurotrophic factor (BDNF) release, suggesting a compensatory mechanism. Moreover, ouabain activated TNF-α-converting enzyme/a disintegrin and metalloprotease 17 (TACE/ADAM17), decreased N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A) expression, and induced anxiety-like behavior in both genotype animals, independent of the presence of TNFR1. However, ouabain induced an increase in interleukin (IL)-1β in the hippocampus, a decrease in IL-6 in serum, and an increase in NMDA receptor subunit 1 (NR1) only in wild-type (WT) mice, indicating that TNFR1 or TNFR2 expression may be important for some effects of ouabain. Collectively, our results indicate a connection between ouabain signaling and TNFR1, with the effect of ouabain partially dependent on TNFR1.

Subchronic exposure to 1,2-naphthoquinone induces adipose tissue inflammation and changes the energy homeostasis of mice, partially due to TNFR1 and TLR4

“…They were validated, displaying a selective lack of TNFR p55 and several deficits in inflammatory responses [45] . TLR4KO and TNFR1KO mice were healthy and have been employed in other studies [10] , [27] . They were backcrossed on C57BL/6 genetic background and bred in the multidisciplinary center for biological research (University of Campinas, SP, Brazil) and the University of São Paulo, Ribeirão Preto, SP, Brazil.…”

O envolvimento da inflamação mediada pela glia nas alterações respiratórias observadas em um modelo murino da Doença de Parkinson.

“…Um modelo animal knockout para TNFR1, como o que utilizamos neste estudo, faz-se de grande utilidade para o estudo da importância da ativação deste receptor na morte neuronal encontrada no modelo de DP induzido por 6-OHDA. Esse modelo animal já foi utilizado na literatura para o estudo da função do TNF-α no desenvolvimento da resposta imunológica e também do papel do TNFR1 na resposta da ouabaína no hipocampo (KINOSHITA et al, 2022;PASPARAKIS et al, 1996) Em ratos que receberam injeção de 6-OHDA com a finalidade de induzir a DP, foi observado um aumento microglial na região da SNc (AKIYAMA; MCGEER, 1989;DEPINO et al, 2003). Com base nisto, buscando entender se há alterações microgliais em regiões neurais de controle respiratório na DP, um estudo ainda não publicado do nosso laboratório demonstrou que em ratos que receberam injeção de 6-OHDA no estriado ocorreu, após 30 e 40 dias, aumento na quantidade de células da microglia no RTN, representado pela densidade da proteína ligante de actina cruzada (Iba1) (Figura 3).…”