Inflammation is a fundamental physiological response that plays a pivotal role in defending our bodies against infections and maintaining tissue homeostasis. However, when this finely tuned response goes awry, it can lead to chronic inflammatory diseases that are often debilitating and, in some cases, life-threatening. Recent advances in our understanding of the molecular mechanisms underlying inflammation have uncovered a class of intracellular protein complexes called inflammasomes, which act as key orchestrators of inflammation. Among these, the NLRP1 and NLRP3 inflammasomes have garnered significant attention due to their involvement in a wide range of inflammatory diseases, including autoimmune disorders, infectious diseases, and even cancer. Inflammasomes are multi-protein complexes that assemble in response to various danger signals, such as pathogen-derived molecules or cellular stress. Once activated, these complexes serve as platforms for the activation of inflammatory caspases, particularly caspase-1, which cleaves pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18). The resulting mature cytokines trigger a potent inflammatory response and, in some cases, pyroptotic cell death, a form of programmed cell death associated with inflammation. Two prominent members of the inflammasome family are NLRP1 and NLRP3. NLRP3, in particular, has been extensively studied and is known to be involved in diverse inflammatory conditions, ranging from gout to neurodegenerative diseases. The NLRP3 inflammasome responds to a wide array of danger signals, including microbial components, crystals, and cellular stress. Consequently, NLRP3 has emerged as an attractive therapeutic target for inflammatory diseases. However, NLRP1, although less well-characterized, has also been implicated in inflammatory responses, autoimmune disorders, and microbial infections.
In a new study published in the Clinical & Translational Immunology Journal and led by Associate Professor Ashley Mansell from the Hudson Institute of Medicine Research at Monash University, researchers have introduced ADS032 as the first potent and specific dual inhibitor of both NLRP1 and NLRP3 inflammasomes. This molecule represents a significant leap forward in our ability to modulate inflammasome activity and opens up exciting avenues for both basic research and clinical applications. One of the key findings of the study is ADS032’s ability to inhibit ASC speck formation, a hallmark of inflammasome activation. ASC specks are high-molecular-weight complexes that serve as platforms for caspase-1 activation. By inhibiting ASC speck formation, ADS032 effectively prevents the downstream inflammatory cascade. This observation underscores the direct action of ADS032 on inflammasome complex formation.
One of the most noteworthy aspects of ADS032 is its efficacy in human cells. While inflammasome research has largely relied on mouse models, translating these findings into therapeutic strategies for human diseases has proven challenging. ADS032 bridges this gap by demonstrating its effectiveness in human macrophages and monocyte-derived macrophages. This human relevance is crucial for the development of potential therapies targeting NLRP1 and NLRP3 in diseases that afflict our species.
ADS032’s dual inhibitory activity against NLRP1 and NLRP3 extends its versatility as a research tool. It provides investigators with a single compound capable of probing the functions of these inflammasomes in various experimental settings. This can significantly streamline research efforts aimed at deciphering the roles of NLRP1 and NLRP3 in different diseases and tissues.
The authors discussed the kinetics of ADS032 inhibition are another intriguing aspect of this compound. ADS032 rapidly inhibits NLRP3 inflammasome activity, even after activation. Importantly, the inhibitory effect remains stable for extended periods. This stability is a desirable trait for potential therapeutic applications, ensuring sustained control over inflammasome-mediated inflammation. Furthermore, ADS032’s reversible inhibition, as demonstrated in experiments, provides a level of control over its action. This feature could be advantageous in situations where transient modulation of inflammasome activity is needed.
The team found that ADS032 to inhibit the formation of ASC specks, which are markers of inflammasome activation. This suggests that ADS032 directly interferes with the assembly of the NLRP3-mediated ASC speck formation. Furthermore, they reported that ADS032 was effective in inhibiting NLRP3-mediated IL-1β secretion in human macrophages and monocyte-derived macrophages, highlighting its potential therapeutic value in human diseases associated with NLRP3 activation. The authors also conducted in vivo experiments, ADS032’s efficacy in reducing systemic and pulmonary inflammation in mouse models is particularly promising. In the context of acute silicosis, a model of human silicosis, ADS032 effectively reduced levels of inflammatory cytokines and cellular infiltrates in the lungs. This demonstrates its potential as a treatment for NLRP3-driven inflammatory diseases that afflict millions worldwide. One of the most intriguing aspects of ADS032 is its capacity to balance the inflammatory response. Inflammation is a double-edged sword. it’s essential for defending against pathogens and promoting tissue repair, but excessive or chronic inflammation can lead to tissue damage and disease. ADS032 appears to walk this fine line adeptly, reducing detrimental inflammation while preserving protective aspects. This ability to ‘rebalance’ the inflammatory response without compromising its beneficial functions makes ADS032 a unique candidate for therapeutic intervention.
A notable achievement in this research is the characterization of ADS032 as the first inhibitor of NLRP1. NLRP1’s role in human diseases has been increasingly recognized, but the lack of pharmacological tools has hindered our ability to study and manipulate its functions. ADS032, by inhibiting NLRP1 in both mouse and human cells, promises to unlock new insights into the diverse roles of NLRP1 in various tissues and diseases.
In summary, ADS032 represents a multifaceted therapeutic approach to inflammatory diseases associated with NLRP1 and NLRP3 inflammasome activation. Its ability to inhibit these inflammasomes in both mouse and human cells, along with its efficacy in reducing inflammation in preclinical models, positions it as a potential game-changer in the field of inflammasome research and therapeutics. Furthermore, its capacity to balance inflammation without compromising protective immune responses opens up possibilities for targeted interventions that harness the benefits of inflammation while mitigating its harmful effects.
Docherty CA, Fernando AJ, Rosli S, Lam M, Dolle RE, Navia MA, Farquhar R, La France D, Tate MD, Murphy CK, Rossi AG, Mansell A. A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases. Clin Transl Immunology. 2023 Jun 22;12(6):e1455. doi: 10.1002/cti2.1455