*4.2. Therapies to Dampen the Hepatic Immune Response*

Direct inhibition of PRRs for the treatment of chronic liver disease has not been a research priority due to their peripheral contribution to disease pathogenesis. It is, however, now becoming evident that PRR activation from both microbial and self-ligands can significantly contribute to liver inflammation and fibrogenesis. TLR-agonistic therapies are currently being actively pursued for cancer therapies/adjuvants (reviewed in Reference [190]). TLR inhibitors, on the other hand, have been studied to a lesser degree in a handful of studies assessing their efficacy in inflammatory and autoimmune disease. Even fewer therapies are being assessed in the context of chronic liver disease, with TLR2/4/9, NLRP3, and STING pathway inhibition garnering some interest from pharmaceutical companies [190].

The humanized TLR2 mAb OPN-305 can achieve significant blockade of TLR2 inflammatory signaling in response to bacterial stimuli in healthy subjects [191], and improved overall response rate in patients with myelodysplastic syndromes that had previously failed hypomethylating agent therapy [192]. While TLR2 blockade has not been assessed in human CLD, the pleiotropic nature of TLR2 suggests that it may benefit inflammatory and fibrotic progression.

Small molecule inhibitors of TLR4, i.e., NI-0101 [193] and Ibudilast [194], are being assessed in extrahepatic disease, and JKB-121, a weak TLR4 antagonist, is currently being assessed in NASH [195]: preliminary results do not support a significant therapeutic benefit of JKB-121, though the study was confounded by a notable improvement in liver inflammation within the placebo group.

TLR9 blockade represents perhaps the most exciting TLR-targeting therapy. The TLR9 inhibitor hydroxychloroquine is currently used as treatment for autoimmune diseases such as rheumatoid arthritis and lupus, allowing potential repurposing for CLD. Furthermore, the novel TLR9 antagonist COV08-0064 has shown promise in animal models of sterile liver inflammation, particularly in the context of fatty liver where it limits inflammasome activation [196,197]. While TLR9 inhibition has yet to be assessed in human CLD, its diversity of microbial ligands, including bacterial, fungal, and phage DNA, will surely make it a candidate for future trials.

Research targeting the NLRP3–inflammasome pathway is undergoing rapid expansion alongside the number of inflammasome-associated diseases. While the NLRP3 inhibitor CP-456,773 was removed from phase II trials for rheumatoid arthritis due to supposed liver toxicity, other inhibitors are in different stages of development for the treatment of gout and Parkinson's disease, among others [198]. In 2018, Genentec acquired San Diego-based Jecure Therapeutics and their portfolio of preclinical NLRP3 inhibitors as a treatment for NASH and hepatic fibrosis [199].

Lastly, the intracellular DNA sensor STING has become a popular target due to its association with autoimmune disease. STING inhibitors have been recently developed [200], and are being actively generated by a number of pharmaceutical companies with the aim of targeting STING-related genetic disease. This compound would have the potential to move towards therapies for CLDs such as NASH and fibrosis in the future [201].
