α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β(1–42)-stimulated murine astrocytes

BACKGROUND: Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β(1–42) (Aβ(1–42)) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ(1–42)-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ(1–42)-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. METHODS: Primary cortical astrocytes from BALB/c mice were stimulated with Aβ(1–42) and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. RESULTS: Our study revealed that A1AT reduces Aβ(1–42)-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ(1–42)-stimulated astrocytes. CONCLUSION: We conclude that Aβ(1–42)-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ(1–42)-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1319-x) contains supplementary material, which is available to authorized users.