NLRC5 Deficiency Reduces LPS-Induced Microglial Activation via Inhibition of NF-κB Signaling and Ameliorates Mice’s Depressive-like Behavior

Abstract

Microglia are believed to be the key immune effectors of the central immune microenvironment, and their dysregulation is associated with neuroinflammation and mood disorders. Nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain-containing five (NLRC5) is a new member of the Nod-like receptor family. Recently, NLRC5 has been reported to be expressed by microglia. Nonetheless, the exact roles of NLRC5 in microglial activation and its function in depression have not been investigated yet. Herein, we found that reducing NLRC5 decreased lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in primary cultured microglia and microglial cell lines but not in bone marrow-derived macrophages (BMDMs). In more detail, reducing NLRC5 diminished the secretion of LPS-induced cytokines by attenuating IKKα/β phosphorylation and inhibiting NF-κB signaling. Moreover, the expression of Nlrc5 in the hippocampus of LPS- or chronic unpredictable mild stress (CUMS)-induced depressive mice was increased. In line with the in vitro findings, Nlrc5 deficiency inhibited microglial activation in the mouse hippocampus and improved LPS- or CUMS-induced depressive-like behaviors. In summary, we demonstrated the critical role of NLRC5 in LPS-induced microglial activation and LPS- or CUMS-induced depressive mouse models.

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

“…Overexpression of the micro-RNAs miR-204-5p or miR-182 inhibited the NF-κB pathway and alleviated depressive behavior [59,60]. NF-κB inhibition was one of the main downstream effects of TREK-1 blockage, IL-4 administration, NLRC5 deficiency, and CTRP3 overexpression, and it was associated with reduced depression-like behaviors in UCMS mice [61][62][63][64]. This makes NF-κB an important target in chronic stress and inflammation studies, particularly because this nuclear factor is upstream of many proinflammatory factors, which will be discussed in the subsections below.…”

GPR55 activation improves anxiety- and depression-like behaviors of mice during methamphetamine withdrawal

“…Increasing hippocampal neurogenesis has been found to improve stress-induced anxiety- and depressive-like behaviors [ 9 , 10 ]. Additionally, activating microglia in the hippocampus promotes the occurrence of depressive-like behaviors [ 11 ], while inhibiting microglial activation and neuroinflammation improves depressive-like behaviors in mice [ 12 ].…”