Learn about how our Gasdermin D (N Terminal) Rabbit Polyclonal Antibody helped researchers evaluate the contribution of the NLRP3 inflammasome in RV-macrophages to PAH-RVF.
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, danger signals, and environmental irritants. It results in the formation and activation of the NLRP3 inflammasome. NLRP3 initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5).
The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. It is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, the production of reactive oxygen species, and lysosomal damage. When activated, gasdermin D (GSDMD) after Asp276 and Asp275, respectively, generates an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death and release of inflammatory cytokines such as interleukin-1β.
Researchers at the Queen’s University found the pathological importance of the NLRP3 inflammasome activation pathway in right ventricular (RV) macrophages for the progression of Pulmonary Arterial Hypertension to Right Ventricular failure (RVF). In their experiments, rats with decompensated RV hypertrophy (RVH) were compared with compensated RVH rats. Echocardiography and right heart catheterization were performed and NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot using HUABIO’s Gasdermin D polyclonal antibody.
Al-Qazazi, Ruaa, et al. show the activation of the NLRP3 inflammasome pathway within the RV macrophages is present in two robust preclinical models of PAH and in patients with
decompensated RVH. In vivo, blockade of the IL6 cytokine pathway via SC-144, or the NLRP3 inflammasome signaling, via MCC950 prevented RV-macrophage accumulation and NLRP3 inflammasome activation while improving RV function. These findings indicate that NLRP3 activation contributes to the pathogenesis of RVF. Moreover, their research suggests that RVF is chamber-specific and can occur due to macrophage-mediated inflammation rather than simply being reflective of a failure to adapt to increased RV afterload.
Al-Qazazi, Ruaa, et al. "Macrophage-NLRP3 activation promotes right ventricle failure in pulmonary arterial hypertension." American Journal of Respiratory and Critical Care Medicine ja (2022).
Swanson, Karen V., Meng Deng, and Jenny P-Y. Ting. "The NLRP3 inflammasome: molecular activation and regulation to therapeutics." Nature Reviews Immunology 19.8 (2019): 477-489.
Kelley, Nathan, et al. "The NLRP3 inflammasome: an overview of mechanisms of activation and regulation." International journal of molecular sciences 20.13 (2019): 3328.
Liu, Xing, et al. "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores." Nature 535.7610 (2016): 153-158.