Unraveling the Converging Roles of ASC-Dependent Inflammasomes, Interleukin-1 Superfamily Members, Serum Amyloid A, and Non-Sterile Inflammation in Disease Pathology and Fibrosis in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Abstract

Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are chronic immune-mediated inflammatory diseases (IMIDs) that affect the gastrointestinal and hepatobiliary systems. They are characterized by persistent inflammation, potentially progressive fibrosis, and an elevated risk of developing cholangiocarcinoma and colorectal cancer. IBD and PSC share phenotypical, genetic, and immunological features, largely due to the central role of immune cell dysregulation. Despite their increasing global prevalence, the underlying drivers remain poorly understood, and effective treatment options are still lacking. Efforts towards an improved comprehension of their pathogenic mechanisms are therefore pivotal. Emerging evidence highlights the role of canonical ASC-dependent inflammasomes-multiprotein bioactive Interleukin (IL)-1-producing complexes of the innate immune system-and serum amyloid A (SAA) as key structures of gastrointestinal and hepatobiliary inflammation, tissue remodeling, stromal crosstalk, and fibrosis. In this review, we explore immunological connections and analogies between IBD and PSC, highlighting the converging roles of canonical ASC-dependent inflammasomes, the IL-1 superfamily, SAA, and sustained gut microbiota-driven chronic inflammation in disease pathology and their surging potential as therapeutic targets across the gut-liver axis.

Keywords: IL-1; IL-1 receptor(R)1; IL-18; IL-33; Interleukin (IL)-1 superfamily; apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); caspase recruitment domain (CARD); caspase-1; chronic inflammation; fibrosis; gut microbiome; inflammasome adapter; inflammasomes; inflammatory bowel disease (IBD); innate immunity; intestinal microbes; non-sterile inflammation; primary sclerosing cholangitis (PSC); pyrin domain (PYD); serum amyloid A (SAA); therapeutic agents.

Figure 1

ASC-dependent inflammasomes in PSC and IBD pathology. Homeostasis and healthy liver and intestinal mucosal state (left) and inflamed/fibrotic disease state (right). A modular structure illustration of the best-known ASC-dependent inflammasomes (middle box).

Figure 2

Promising targets along the ASC-inflammasomes and Interleukin-1/18 signaling cascade reported in recent pre- and clinical IBD and PSC treatment approaches. (A) Schematic of myeloid cell-derived ASC-inflammasomes and molecule blockade. (B) Representation of presumed inhibitory (inhibitory signs) and supplementary/agonism (green arrows) approaches among mucosal and hepatobiliary compartments along the gut–liver axis. Of note, agents may act in various cell types simultaneously. Details on described agents and their mechanism are listed in Table 1.