Neuroinflammation is thought to drive changes in neurotransmitters and neurocircuits that lead to major depressive disorder (MDD). In this article, we provide direct evidence that microglial Pdcd4 mediates neuroinflammation-associated microglia activation and consequent depressive-like behaviors in mice by interrupting the PPARγ mediated IL-10 transcription.
We confirmed Pdcd4 is involved in inflammatory-related depression via regulating microglia activation. Regardless of the devasting role of neuronal Pdcd4 in CRS-induced depression[10, 11], we found neuronal Pdcd4 knockout didn’t protect mice from LPS-induced depressive-like behaviors. LPS challenge, mimicking an acute inflammatory response, stimulated peripheral immunity, and subsequently evoked central inflammation and depressive-like behaviors[19]. Mechanically, LPS stress caused more microglia activation and stronger cytokines expression than chronic restraint stress (CRS), resulting in a significant difference between the LPS and CRS models in aspects of intensity and duration of stress[20]. In addition, in this study, we found the overexpressed Pdcd4 in the PFC but not in the HIP caused by the LPS challenge, consequently contributing to enhanced neuroinflammation reaction. Though the prefrontal cortex, hippocampus, striatum, and hypothalamus are well-known brain areas that have a relationship with depression, multiple studies have referred to significant cytokines expression and microglia activation in the PFC rather than in the HIP[20]. We speculated the Pdcd4 expression profile may contribute to various neuroinflammatory responses in different brain regions during stress. Therefore, digging out the upstream regulatory mechanism for Pdcd4 expression helps us to uncover diverse reflections of brain areas on stress. Recently report found LPS required the MAPK/NF-κB signaling activation to boost Pdcd4 expression in microglia, perhaps digging out the NF-κB signaling response pattern during the LPS challenge will help us to answer that question[21]. Overall, we discovered only microglial Pdcd4 of the PFC was responsible for LPS-related depressive-like behavior, uncovering the diverse functions of Pdcd4 in nerve cells and brain regions, especially the immunoregulation role of Pdcd4 in PFC of the neuroinflammation associated depression.
Secondly, we discovered the involvement of the Pdcd4/PPARγ axis in depressive-like behavior. A previous study has referred that lncRNA-H19 facilitated Pdcd4 expression in microglia via sponging miR-21, which initiated the Ischemia-reperfusion (I/R)-induced inflammation[22]. However, the specific mechanism underlying Pdcd4-regulated neuroinflammation in depression is still unknown. We found that Pdcd4 promotes inflammation by prohibiting PPARγ nuclear translocation. PPARγ is one of the three isoforms of PPARs. PPARγ is activated by thiazolidinediones such as pioglitazone and is applied for insulin resistance treatment. Previous reports have demonstrated that neuronal PPARγ directly mediated stress-induced emotional disorders and PPARγ agonists have an anti-depressive effect, suggesting the essential role of PPARγ in depression[23]. Based on the enrichment of PPARγ expression in microglia, PPARγ also has anti-inflammatory properties[24]. In this article, we found microglial Pdcd4 deletion abolished LPS-induced microglia activation via up-regulating PPARγ expression and nucleus translocation. We thought there is a causal link between PPARγ up-regulation and nucleus transportation, for rapidly ubiquitin-proteasome mediated degradation of cytosol distributed PPARγ [25]. E3 RING ubiquitin ligases have reported, such as NEDD4-1, TRIM25, FBXO9, MKRN1, CUL4B, and FBXO4, regulate PPARγ protein levels which contribute to adipogenesis[26–31]. Nevertheless, whether the protein degradation of PPARγ is required for microglia activation and polarization is still unknown. In conclusion, microglial PPARγ is necessary for neuroinflammatory response.
Thirdly, we illustrated Daxx as an adaptor, which is critical for PPARγ cytosol-nuclear shuttle. Daxx is dynamically recruited by PPARγ and induced translocation of PPARγ into the nuclear compartment. Due to Pdcd4 and Daxx interaction, Pdcd4 decreases the half-life of Daxx, further, it disrupts the complex of PPARγ/Daxx formation[18]. Therefore, Pdcd4 is a switch for Daxx-mediated PPARγ nuclear translocation, and Pdcd4 deletion stabilizes PPARγ in the nuclei. As referred before, DAXX in macrophage, as a co-repressor, suppresses the expression of NF-κB-targeted pro-inflammatory genes by coupling with histone acetylation eraser and DNA hypermethylation[32]. Hence, we provided a potential mechanism of PPARγ for inhibiting inflammation via Daxx-related DNA epigenetic modification. Further studies will be needed to determine the roles of PPARγ in the DAXX-mediated activation of proinflammatory gene transcription.
Finally, our data demonstrated the antidepressant role of IL-10. A study on IL-10 knockout mice shows an increase in depressive-like behaviors that are reversed by IL-10 injection[33]. In addition, the drugs for depression treatment, such as Fluoxetine and Sertralin, have displayed anti-inflammatory properties, including IL-10 up-regulation[1]. Despite these findings, the mechanisms that underlie these changes related to IL-10 remain to be clarified. Our finding suggests that following the dysfunction of PPARγ, the expression of IL-10 was prohibited in microglia during the depression. Supporting the research about pioglitazone ameliorating depression-like behaviors for the neuroprotective phenotype of microglia, we provided direct evidence to prove the anti-inflammatory role of PPARγ for increasing IL-10 mRNA transcription by binding to IL-10 gene promoter. Overall, we emphasized the therapeutic role of IL-10 for depression.
In conclusion, to the limitation of traditional therapy of depression, we are urged to find the new pathological mechanism of the disease. Our findings show that neuroinflammatory reaction, including microglia activation and cytokines secretion is integrated into depressive-like behaviors via activation of Pdcd4 mediated PPARγ/IL-10 axis.