Toll-like receptor 4 in the interface between neuroimmune response and behavioral alterations caused by stress

Abstract

Different stressors can elicit neuroinflammatory responses modulated by innate immunity receptors, such as the family of Toll-like receptors (TLRs). The TLR4, a pattern recognition receptor (PRR), is involved in many diseases, such as inflammatory and central nervous system (CNS) diseases. Stress exposure can regulate the expression of PRRs, including TLR4, in the brain of animals, especially in the hippocampus and prefrontal cortex. Moreover, TLR4 modulates behavior and neuroinflammatory responses in the brain. In addition, to TLR4, the endocannabinoid (eCB) system plays a role in stress response and immunity, acting as a regulatory, stress-buffer system. This system is involved in many TLRs-mediated immune responses, such as microglia activation. Therefore, pharmacological approaches targeting the eCB system could modulate neuroinflammatory responses to stress by interfering with the TLR4 pathway. Although the connection between TLR4, stress, and neuroinflammation is well documented, almost no pre-clinical studies investigate the possible direct relationship between TLR4, behavior, stress, and the eCB system. Studies exploring the relationship between stress, neuroinflammation, TLR4, and the eCB system were searched using Pubmed, Web of Science, and Embase databases. Based on this search, this review is focused on the involvement of TLR4 receptors and signaling in neuroinflammation and the behavioral consequences of stress exposure. Moreover, evidence of the eCB system modulating TLR4-mediated responses was brought to the attention, pointing out a possible regulatory role of these responses by eCBs in behavior changes related to mood disorders.

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

“…Among TLRs, TLR4 stands out for its prominent involvement in stress-induced neuroinflammatory responses and subsequent behavioral alterations. Moreover, the activation of the TLR4/MyD88/NF-κB pathway has been linked to chronic unpredictable mild stress in rat models [154,156]. In a mouse model of hippocampal neuroinflammation, the activation of the TLR4/TRAF6/NF-κB signaling pathway, triggered by LPS, emerges as a significant contributor to depressivelike behaviors [155].…”

Avaliação das consequências comportamentais da administração de um inibidor da via do TLR4 no córtex pré-frontal medial após exposição ao estresse e possível envolvimento do sistema endocanabinoide

“…Além disso, modelos genéticos também são utilizados, como camundongos knockout (KO) para TLR4 e camundongos C3H/HeJ; no último, o TLR4 tem uma resposta defeituosa ao LPS (Gárate, I. et al, 2013). Vários estudos mostram que TLR4 KO é resistente ao efeito comportamental do estresse e tem níveis mais baixos de neuroinflamação (para revisão, ver (Souza-Junior et al, 2022). Os camundongos TLR4 KO demonstram resistência ao comportamento depressivo no paradigma do desamparo aprendido e exibem uma resposta de citocinas atenuada ao estresse, caracterizada por níveis mais baixos de TNF-α, IL-6 e IL-1β no hipocampo em comparação com camundongos do tipo selvagem (Cheng et al, 2016).…”

“…Em condições normais, o eixo HPA regula e modula o equilíbrio imunológico através dos glicocorticoides. No entanto, eventos estressantes podem levar à hiperatividade do eixo HPA e desencadear aumento da resposta imunológica central e periférica (para revisão ver(Souza-Junior et al, 2022).…”