Implication of NLRP3 inflammasome in lipopolysaccharide-induced depressive like behaviors

Abstract

For many years, central nervous system (CNS) was considered to be immune privileged, however, many reports now suggest that immune and inflammatory response can take place in the brain region. although mechanism of neuroinflammation remains to be unknown. Neuroinflammation is mediated by brain resident glial cells, mainly microglial cells and astrocytes, and infiltrated macrophages. These CNS-innate immune cells sense danger signals such as ATP and misfolded protein and cascade pro-inflammatory signaling. Inflammasome is cytosolic multi-protein complex that triggers caspase-1 activation and interleukin-1β (IL-1β) and interleukin-18 (IL-18) secretion in response to pathogen associated molecular patterns (PAMPs) or danger associated molecular patterns (DAMPs). NLRP3 inflammasome, which is best characterized, is known to be involved in pathogenesis of neurological disorders. Recently, several reports suggest that excessive activation of NLRP3 inflammasome upon amyloid-β plaque and α-synuclein aggregation leads to pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Depressive disorder is one of the commonest psychiatric disorders, which is complex disorder with no established pathophysiological mechanism. Emerging papers are suggesting that inflammatory response can lead to comorbid depressive disorders. Recently, clinical data show that patients with depression have higher levels of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factorα (TNFα) in peripheral serum. The kynurenine/tryptophan metabolism is known to be one of the important mechanisms, which mediates relevance of inflammation to depressive behaviors. Indoleamine 2,3-deoxygenase (IDO) – a key enzyme of kynurenine pathway in the CNS – is known to be driven by pro-inflammatory cytokines. Increase of IDO in glial cells leads to production of kynurenic acid (KA) and quinolinic acid (QA), which contribute to neuronal dysfunction, while the increase of IDO in neurons leads to 5-HT deficiency. Here, we demonstrated that NLRP3 inflammasome is closely implicated in lipopolysaccharide (LPS)-induced depressive like behaviors. Deficiency of Nlrp3 in mice demonstrated a significantly reduced depressive like behaviors after LPS-administration. Deficiency of Nlrp3 reduced recruitment of immune cells into brain hippocampus of LPS-induced depressive mouse. Moreover, we observed that active caspase-1 was significantly reduced in the hippocampus of Nlrp3-/- mice compared to wild type mice. Mechanistically, IDO was transcriptionally and functionally up-regulated in brains of LPS-injected WT mice, while it was not in Nlrp3-/- mice. In primary mixed glial cultures, we observed that NLRP3 inflammasome-activating stimulation increased the IDO gene expression and this effect was caspase-1 dependent. However, Recombinant IL-1β or IL-18 did not directly regulate IDO expression. Collectively, all our results indicate that NLRP3 inflammasome could contribute to progression of depressive like behaviors via regulating IDO activity in glial cells.