The outbreak of diseases ordinarily results from the disruption of the balance and harmony between hosts and pathogens. Devoid of adaptive immunity, shrimp rely largely on the innate immune system to protect themselves from pathogenic infection. Two nuclear factor-κB (NF-κB) pathways, the Toll and immune deficiency (IMD) pathways, are generally regarded as the major regulators of the immune response in shrimp, which have been extensively studied over the years. Bacterial infection can be recognized by Toll and IMD pathways, which activate two NF-κB transcription factors, Dorsal and Relish, respectively, to eventually lead to boosting the expression of various antimicrobial peptides (AMPs). In response to white-spot-syndrome-virus (WSSV) infection, these two pathways appear to be subverted and hijacked to favor viral survival. In this review, the recent progress in elucidating microbial recognition, signal transduction, and effector regulation within both shrimp Toll and IMD pathways will be discussed. We will also highlight and discuss the similarities and differences between shrimps and their Drosophila or mammalian counterparts. Understanding the interplay between pathogens and shrimp NF-κB pathways may provide new opportunities for disease-prevention strategies in the future.

/pdf/the-two-nf-kb-pathways-regulating-bacterial-and-wssv-zrq25wfld0.pdf

The Two NF-κB Pathways Regulating Bacterial and WSSV Infection of Shrimp.

Simple Summary In this study, we investigated the potential of TLR4 to improve the treatment of hepatocellular carcinoma (HCC). HCC is a serious health concern worldwide, and finding new ways to combat it is crucial. Our study focused on understanding how TLR4 can enhance the effectiveness of immunotherapy, a treatment approach that harnesses the body’s immune system to fight cancer cells. We demonstrated that targeting TLR4 can stimulate the immune response against HCC cells, leading to their destruction. This exciting finding suggests that TLR4 could serve as a valuable target for developing new therapies for HCC. The implications of this study extend beyond the realm of medical research. If successful, these new strategies could offer renewed hope to HCC patients and potentially improve the overall survival rates. Furthermore, the insights gained from our study may pave the way for similar approaches in treating other types of cancer. In summary, our research highlights the significant role of TLR4 in enhancing immunotherapy for HCC. This knowledge brings us one step closer to developing more effective treatments and improving the lives of cancer patients. Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

/pdf/the-role-of-tlr4-in-the-immunotherapy-of-hepatocellular-3ah5avr5.pdf

The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Toll-like receptor 4 (TLR4) plays an important role as a key signal-receiving transmembrane protein molecule in the liver, and substances that target the liver exert therapeutic effects via TLR4-related signaling pathways. This article provides a comprehensive review of targeting the TLR4 signaling axis to play an important role in the liver based on endogenous substances. Articles were divided into 5 major types of liver disease, acute liver injury, viral hepatitis, alcoholic and non-alcoholic liver disease, cirrhosis, and liver cancer, to elucidate how various endogenous substances affect the liver via the TLR4 pathway and the important role of the pathway itself in liver-related diseases to discover the potential therapeutic implications of the TLR4-related pathway in the liver. The results indicate that activation of the TLR4-related signaling axis primarily plays a role in promoting disease progression in liver-related diseases, and the TLR4/MyD88/NF-κB axis plays the most dominant role. Therefore, exploring the full effects of drugs targeting the TLR4-related signaling axis in the liver and the new use of old drugs may be a new research direction. 

Role of targeting TLR4 signaling axis in liver-related diseases.

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics. 

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

Despite the advances in the medical field so far, cancer remains a global health priority even now. Considering the drug resistance and the failure of cancer therapies to achieve complete eradication of cancer cells in certain populations, developing molecules that induce programmed cell death or apoptosis has been the focus of cancer research for several decades. Apoptosis evasion is one of the hallmarks of cancer cells, and efforts continue to achieve complete annihilation of cancer cells through selective killing. On the other hand, autophagy, a mode of cell degradation, is considered a double-edged sword. Recent studies show that autophagy also can be manipulated to selectively target cancer cells based on the tumor microenvironment and cellular context. Studies show that autophagy is an evolutionarily conserved process initiated during stress response and has enormous importance in maintaining physiological balance. Most importantly, the dynamic equilibrium between apoptosis and autophagy is crucial in maintaining cellular homeostasis. Although a ‘cell eating’ process, the fate of autophagic cells depends entirely on the nature of stress and the extent of crosstalk between autophagy. This understanding is of immense significance when designing therapeutic interventions targeting apoptosis and autophagy.  Currently, several studies are ongoing to gain insights into the role of autophagy in cancer initiation, invasion, progression, angiogenesis, and metastasis.  This review focuses on the two major cell death mechanisms, apoptosis and autophagy, in the context of cancer, their crosstalk, and the therapeutic interventions targeting both modes of cell death.

Apoptosis and Autophagy: Therapeutic Implications in Cancer

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)–primed Fadd−/−Ripk3−/− myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd−/−Ripk3−/− macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic shock in Fadd−/−Ripk3−/− mice, implying distinct death processes in other cell types. Cathepsin-B contributes to IETD-mediated inflammasome activation, as its inhibition or down-regulation limited IETD-elicited IL-1β production. Therefore, the autophagy and cathepsin-B axis represents one of the pathways leading to atypical inflammasome activation when apoptosis and necroptosis are suppressed and capase-8 is inhibited in myeloid cells.

https://www.science.org/doi/pdf/10.1126/sciadv.abn9912?download=true

Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells

O019 TLR4-mediated IKK and MAPK activation is regulated by differential post-translational modification of TAK1

Chronic inflammation caused by liver damage or infection plays an important role in the development and progression of hepatocellular carcinoma (HCC). The activation of Toll-like receptors 4 (TLR4) is involved in HCC tumorigenesis. Moreover, high TLR4 expression in HCC has been linked to poor prognosis. Although the expression of TLR4 in HCC is relatively low compared to hematopoietic cells, it is important to explore the molecular mechanism leading to the elevation of TLR4 in HCC. In this study, we aimed to investigate the positive regulating loop for TLR4 expression in HCC in response to chronic inflammation. Our results confirm that the mRNA expression of TLR4 and proinflammatory cytokines, including interleukin 6 (IL6) and C-C motif chemokine ligand 2 (CCL2), positively correlate in human HCC samples. High TLR4 expression in HCC is more susceptible to lipopolysaccharide (LPS); TLR4 activation in HCC provides growth and survival advantages and thus promotes tumorigenesis. It has been shown that the LIN28/let-7 microRNA (miRNA) axis is a downstream effector of the TLR4 signal pathway, and let-7 miRNA is a potential post-transcriptional regulator for TLR4. Thus, we investigated the correlation between TLR4 and LIN28A mRNA and let-7g miRNA in HCC clinical samples and found that the expression of TLR4 was positively correlated with LIN28A and negatively correlated with let-7g miRNA. Moreover, by culturing PLC/PRF5 (PLC5) HCC cells in low-dose LPS-containing medium to mimic chronic inflammation for persistent TLR4 activation, the mRNA and protein levels of TLR4 and LIN28A were elevated, and let-7g miRNA was decreased. Furthermore, the 3’ untranslated region (3’UTR) of TLR4 mRNA was shown to be the target of let-7g miRNA, suggesting that inhibition of let-7g miRNA is able to increase TLR4 mRNA. While parental PLC5 cells have a low susceptibility to LPS-induced cell growth, long-term LPS exposure for PLC5 cells leads to increased proliferation, cytokine expression and stemness properties. In conclusion, our studies demonstrate positive feedback regulation for chronic TLR4 activation in the modulation of TLR4 expression level through the LIN28A/let-7g pathway in HCC and suggest a connection between chronic inflammation and TLR4 expression level in HCC for promoting tumorigenesis.

/pdf/persistent-tlr4-activation-promotes-hepatocellular-carcinoma-29e9cm57.pdf

Persistent TLR4 Activation Promotes Hepatocellular Carcinoma Growth through Positive Feedback Regulation by LIN28A/Let-7g miRNA

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Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells

O019 TLR4-mediated IKK and MAPK activation is regulated by differential post-translational modification of TAK1

Persistent TLR4 Activation Promotes Hepatocellular Carcinoma Growth through Positive Feedback Regulation by LIN28A/Let-7g miRNA