Letter to the Editor: Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation

Abstract

To the editor, We read with great interest the article by Ribeiro et al, that investigated the role of extracellular ASC (ex-ASC) specks in prolonged systemic and liver inflammation in alcohol-associated hepatitis. The authors concluded that the presence of NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) in ex-ASC specks is essential to amplify the sustained inflammasome activation and IL-1β production in alcohol-induced liver inflammation. [1] However, we have some concerns about this conclusion.First, the current study reported that the low level of NLRP3 in hepatocyte-derived apoptosis-associated speck-like protein containing a CARD (ASC) specks was responsible for the different inflammasome activation effects between macrophages and hepatocytes. However, as shown in Figure 6F of Ribeiro et al, even if the NLRP3-overexpressing hepatocyte-derived ASC specks still failed to induce IL-1β release, a very limited explanation was provided for this result. Therefore, whether NLRP3 is critical in mediating ex-ASC specksinduced persistent inflammation in adjacent cells remains to be further clarified. Importantly, it would be more convincing to evaluate the effect of ASC specks derived from NLRP3-deficient macrophages on inflammation activation in both macrophages and hepatocytes.Second, only the protein composition of ASC specks was analyzed in macrophage and hepatocyte-derived ASC specks, while the oligomerization degree of ASC specks was not mentioned. Of note, recent studies have shown that the oligomeric states of ex-ASC specks are crucial in regulating inflammasome activation. ASC specks with a low degree of oligomerization are more prone to interaction with pro-caspase-1 and promote its activation. [2] Moreover, the ASC oligomers can change their structure independently of NLRP3 to promote the recruitment of pro-caspase-1. [3] Thus, to fully explain the different biological effects between macrophage-and hepatocyte-derived ASC specks, it is necessary to determine the oligomerization degree of ex-ASC specks in depth, which will have a notable impact on the final result.Third, in this research, MCC950 inhibition is not sufficient to prove that NLRP3 level in liver-derived ex-ASC specks is critical in amplifying systemic and liver inflammation in vivo. Since other tissues may also contribute to the release of ex-ASC specks to circulation. Therefore, further validation is needed, such as using myeloid-cell-specific or hepatocyte-specific NLRP3-deficient mice to unveil the role of NLRP3 in macrophage and hepatocyte-derived ex-ASC specks on alcohol-induced adjacent cell inflammation.In summary, this study provides a novel discovery on the role of ex-ASC specks in sustained inflammation in alcohol-associated hepatitis. However, further studies are required concerning the above issues to enhance the conclusions of this study. AUTHOR CONTRIBUTIONSJiayan Shen and Kaiyue Zhang contributed equally as co-first authors.