Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Abstract

Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and antiinflammatory therapies in acute organ failure.

STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury

“…Numerous reports have confirmed that STING can be activated by cyclic dinucleotides and/or double-stranded (ds) DNA produced by bacteria or virally transfected cells [ 59 – 61 ]. STING has also been shown to be upregulated by self-DNA released during cell death in animal models of liver disease [ 62 – 64 ] and UV-irradiation-induced cell death [ 65 ]. More recently, activation of the STING-IRF3 axis has been implicated in driving the inflammatory response and apoptosis in fatty liver disease [ 66 ].…”

Changes in expression of genes related to caspases and BCL-2 family in RPTEC treated with amphotericin B and its modified forms

“…Simultaneously, there was increased activity of the CFLAR gene. This gene encodes a homologue of caspase-8 and blocks its pro-apoptotic activity in response to receptor signalization [37].…”

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

“…One of the downstream pathways is myeloid differentiation factor 88 (MyD88)-dependent which is linked with the translocation of nuclear factor-κB (NF-κB), resulting in the release of proinflammatory cytokines including tumor necrosis factors α (TNFα) and interleukin-1β (IL-1β). [114,116] Moreover, another PRR, cytoplasmic nucleotidebinding oligomerization domain (NOD)-like receptors (NLRs), is involved in a wide range of immune and cell death pathways. Furthermore, the TLRs pathway comprise of MyD88dependent pathway and TRIF-dependent pathway.…”

“…Cytosolic dsDNA, including microbial DNA and self DNA, can induce an immune response via DAMPs and active stimulator of interferon genes (STING) via cGAS, which are crucial for cell death in vitro. Cellular FLICE‐inhibitory protein (cFLIP) was reported to be associated within this inflammation and the immune response process and can act as a drug target for NASH . Moreover, another PRR, cytoplasmic nucleotide‐binding oligomerization domain (NOD)‐like receptors (NLRs), is involved in a wide range of immune and cell death pathways.…”