Porcine reproductive and respiratory syndrome virus (PRRSV) infection results in extensive tissue inflammation and damage, which are believed to be responsible for increased susceptibility to secondary infection and even for death. However, its pathogenic mechanisms are not fully understood. To explore the mechanism underlying the PRRSV-induced tissue inflammation and damage, we investigated whether PRRSV activates porcine alveolar macrophage (PAM) inflammasomes which mediate por-IL-1β maturation/release and subsequently induce tissue inflammation and injury. Our results showed that PRRSV and its small envelope protein E significantly increased IL-1β release from LPS-primed PAMs; however, only PRRSV not protein E significantly increased IL-1β release from no-LPS-primed PAMs, which indicates PRRSV can activate inflammasomes of PAMs by its encoded protein E. These results provide a molecular basis for the pathogenic mechanism of PRRSV on inducing extensive tissue inflammation and damage, and suggest that the inflammasome may provide a potential therapeutic target for PRRS prevention and treatment.

Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1β and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage — events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome ‘priming’ and ‘activation’ steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.

Inflammasomes comprise a family of cytosolic multi-protein complexes that modulate the activation of cysteine-aspartate-specific protease 1 (caspase-1) and promote the maturation and secretion of interleukin (IL)-1β and IL-18, leading to an inflammatory response. Different types of inflammasomes are defined by their sensor protein which recognizes pathogenic ligands and then directs inflammasome assembly. Although the specific molecular mechanisms underlying the activation of most inflammasomes are still unclear, NLRC4 inflammasomes have emerged as multifaceted agents of the innate immune response, playing important roles in immune defense against a variety of pathogens. Other studies have also expanded the scope of NLRC4 inflammasomes to include a range of inherited human autoimmune diseases as well as proposed roles in cancer. In this review article, we provide an updated overview of NLRC4 inflammasomes, describing their composition, activation mechanisms and roles in both microbial infections and other disease conditions.

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