Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice

Abstract

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

“…It has recently been shown that most, if not all, antidepressant drugs bring about their antidepressant effects by binding the tyrosine kinase receptor 2 (TrkB), a molecule tied to the action of BDNF [ 127 , 128 ]. The findings of the studies reviewed here quite match this concept; increased TrkB/BDNF signalling was related to antidepressant effects, and low levels were associated with depressive behaviour [ 11 , 50 , 66 , 69 , 84 , 93 , 103 , 111 , 120 ]. Increased activity also of protein kinase B (Akt-1), which is an antioxidant in the wingless-GSK pathway and carries on some of the biological [ 128 , 129 , 130 ] and clinical [ 131 ] actions of lithium, which also inhibits GSK-3β [ 132 , 133 , 134 ], was found to be associated with antidepressant effects in the studies included in this review [ 42 , 45 , 47 , 74 , 75 , 93 , 94 , 110 , 119 ].…”

“…The studies included here were based on different animal depression paradigms, with many studies using stress-induced DLB, mostly elicited by LPS [ 40 , 43 , 51 , 53 , 58 , 59 , 63 , 65 , 67 , 73 , 75 , 79 , 85 , 88 , 95 , 105 , 106 , 125 ], or through corticosterone or cortisol [ 44 , 46 , 80 , 87 , 98 ], while other studies used chronic unpredictable mild stress [ 61 , 72 , 76 , 83 , 93 , 96 , 97 , 99 , 100 , 101 , 106 , 108 , 111 , 122 , 124 ] or social defeat stress [ 50 , 52 , 88 , 102 , 107 , 120 ]. Two studies used tumour-related depression models [ 71 , 91 ], while just one study each used post-ovariectomised depression [ 121 ], pentylenetetrazol-induced seizures [ 116 ], maternal separation [ <...…”

“…Two studies used tumour-related depression models [ 71 , 91 ], while just one study each used post-ovariectomised depression [ 121 ], pentylenetetrazol-induced seizures [ 116 ], maternal separation [ 117 ], and olfactory bulbectomy [ 113 ] models ( Table 1 ). Various studies used Nrf2 knock-out animals [ 49 , 62 , 84 , 88 , 120 ] or knock-out of the inflammation and histone methylation modulator protein arginine methyltransferase [ 67 ]. Nrf2 knock-out or knock-down apparently impairs neurochemical indexes and behavioural test performance, while protein arginine methyltransferase knock-out decreases depressive indexes [ 67 ].…”

Caspase-1 modulates chronic restraint stress-induced depression and GABAergic dysfunction via regulating GAD67 in the hippocampus

“…SPT was used to assess anhedonia according to previously established protocols [8,30]. The mice were subjected to two bottles lled with either 1% sucrose or water following 24 h period of food and water deprivation.…”

Tryptophan metabolism as bridge between gut microbiota and brain in chronic social defeat stress-induced depression mice

“…According to the reports of World Health Organization, depression affects about 3.8% of the population and causes huge economic burdens on individual, family and society. However, the pathogenesis of depression is yet unclear (He et al, 2022;Zhong et al, 2022), which results in two serious problems: i) only about 70% patients response to the first-line antidepressants; and ii) no objective laboratory methods are developed to diagnose depression Mojtabavi et al, 2022;Tian et al, 2023). Therefore, it is urgently needed to further explore the pathogenesis of depression.…”