ABSTRACT
Background: Inflammation may play a significant role in the pathogenesis of depression, although the molecular target for the treatment of inflammation-mediated depressive symptoms remains to be elucidated. Recent studies have implicated the NLRP3 inflammasome in various psychiatric disorders, including depression. However, the underlying mechanism by which NLRP3 inflammasome activation mediates the progression of depressive-like behaviors remains poorly understood. Methods: We examined whether NLRP3 deficiency influenced depressive-like behaviors and cerebral inflammation following systemic administration of lipopolysaccharide in mice. To further assess the contribution of the NLRP3 inflammasome to the progression of depression, we evaluated the effects of NLRP3 signaling on levels of indoleamine 2,3-dioxygenase. Results: Nlrp3-deficient mice exhibited significant attenuation of depressive-like behaviors and cerebral caspase-1 activation in a lipopolysaccharide-induced model of depression. Treatment with the antidepressant amitriptyline failed to block NLRP3-dependent activation of caspase-1, but inhibited lipopolysaccharide-promoted production of interleukin-1ß mRNA via suppressing NF-κB signaling in mouse mixed glial cultures. Interestingly, lipopolysaccharide administration produced NLRP3-dependent increases in indoleamine 2,3-dioxygenase expression and activity of mouse brain. Furthermore, inflammasome-activating stimulations, but not treatment with the inflammasome product interleukin-1ß, triggered indoleamine 2,3-dioxygenase mRNA induction in mixed glial cells. Conclusions: Our data indicate that the NLRP3 inflammasome is significantly implicated in the progression of systemic inflammation-induced depression. NLRP3-dependent caspase-1 activation produced significant increases in indoleamine 2,3-dioxygenase levels, which may play a significant role in lipopolysaccharide-induced depression. Collectively, our findings suggest that indoleamine 2,3-dioxygenase is a potential downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors.
Subject(s)
Depression/chemically induced , Depression/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Lipopolysaccharides/toxicity , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Amitriptyline/therapeutic use , Analysis of Variance , Animals , Brain/cytology , Caspase 1/metabolism , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Activation/genetics , Gene Expression Regulation, Enzymologic/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Neuroglia/drug effects , Neuroglia/metabolism , RNA, MessengerABSTRACT
Emerging reports demonstrate that deregulated NLRP3 inflammasome activation is implicated in a variety of inflammatory and metabolic disorders, but the molecular mechanism underlying NLRP3 inflammasome regulation remains uncertain. Here, we present evidence that histone deacetylase 6 (HDAC6) inhibits the activation of NLRP3 inflammasome through its direct association with NLRP3. ShRNA-mediated knockdown of HDAC6 in bone marrow-derived macrophages (BMDMs) showed a significant increase in caspase-1 activation and interleukin-1 beta (IL-1ß) secretion in response to NLRP3-activating stimulations, but not to absent in melanoma 2 (AIM2)-activating stimulation. In addition, knockdown of HDAC6 in BMDMs enhanced the oligomerization of ASC upon LPS/nigericin stimulation. The augmented NLRP3 inflammasome activation seen in HDAC6-knockdown BMDMs is independent of the deacetylase activity of HDAC6. Instead, HDAC6 directly associates with NLRP3 through its ubiquitin-binding domain. Moreover, PR619 treatment (deubiquitinase inhibitor) resulted in the elevation in the interaction of NLRP3 with HDAC6 and the decrease in NLRP3-dependent caspase-1 activation. Taken together, our results indicate that HDAC6 negatively regulates NLRP3 inflammasome activation through its interaction to ubiquitinated NLRP3.
