MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

Yang, Dujiang; Wang, Xiaodong; Fu, Xiao-Ying; Lu, Honglin; Zhou, Zong-Guang; Liu, Yong

doi:10.21037/atm-22-5134

Cited by 3 publications

(4 citation statements)

References 46 publications

(54 reference statements)

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“…Necroptosis has been reported to be the predominant type of acinar cell death in caerulein-induced acute pancreatitis [ 9 , 36 , 37 ]. The severity of caerulein-induced acute pancreatitis can be reduced by pharmacological inhibition of RIPK1 [ 36 , 38 – 40 ]. We thus explored whether Vemurafenib could mitigate the tissue injury in caerulein-induced acute pancreatitis model (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist

Sun,

Ma,

et al. 2023

Cell Death Dis

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Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.

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Section: Resultsmentioning

confidence: 99%

Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist

Sun,

Ma,

et al. 2023

Cell Death Dis

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“…These results suggest a cell specific effect of the TLR/MYD88/IRAK pathway. Whereas the MYD88/IRAK pathway activates in acinar cells a damage-limiting anti-stress response 15 , 32 , the same pathway leads in cells of the innate immune system to an increased pro-inflammatory response 8 . In the severe model of AP, pro-inflammation reaches a systemic level, accompanied by a cytokine storm and severity driving SIRS, whereas a limited pathway activation enhances the clearance of pancreatic necrosis and does not necessarily result in a systemic hyperinflammation.…”

Section: Discussionmentioning

confidence: 99%

IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity in acute pancreatitis

Thiel

Asgarbeik

Glaubitz

et al. 2023

Sci Rep

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Acute pancreatitis (AP), which is characterized by self-digestion of the pancreas by its own prematurely activated digestive proteases, is a major reason for hospitalization. The autodigestive process causes necrotic cell death of pancreatic acinar cells and the release of damage associated molecular pattern which activate macrophages and drive the secretion of pro-inflammatory cytokines. The MYD88/IRAK signaling pathway plays an important role for the induction of inflammatory responses. Interleukin-1 receptor associated kinase-3 (IRAK3) is a counter-regulator of this pathway. In this study, we investigated the role of MYD88/IRAK using Irak3−/− mice in two experimental animal models of mild and severe AP. IRAK3 is expressed in macrophages as well as pancreatic acinar cells where it restrains NFκB activation. Deletion of IRAK3 enhanced the migration of CCR2+ monocytes into the pancreas and triggered a pro-inflammatory type 1 immune response characterized by significantly increased serum levels of TNFα, IL-6, and IL-12p70. Unexpectedly, in a mild AP model this enhanced pro-inflammatory response resulted in decreased pancreatic damage, whereas in a severe AP model, induced by partial pancreatic duct ligation, the increased pro-inflammatory response drives a severe systemic inflammatory response syndrome (SIRS) and is associated with an increased local and systemic damage. Our results indicate that complex immune regulation mechanism control the course of AP, where moderate pro-inflammation not necessarily associates with increased disease severity but also drives tissue regenerative processes through a more effective clearance of necrotic acinar cells. Only when the pro-inflammation exceeds a certain systemic level, it fuels SIRS and increases disease severity.

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“…A lack of MyD88 in cells might lead to the MyD88-independent pathway, initiating the late phase of the TLR4 signaling pathway ( 22 ). Additionally, CD14 mediates the internalization of the TLR4/MD-2/LPS complex into endosomes ( 23 ).…”

Section: Lps Recognition and Response Mechanismmentioning

confidence: 99%

“…The MyD88-dependent pathway is indispensable for the production of inflammatory cytokines (18,19). After TIRAP (also known as MAL) is recruited to the TLR4, MyD88 triggers the formation of a complex by binding to serine/threonine kinases, interleukin-1 receptor-associated kinases 2 and 4 (IRAK2 and IRAK4) (20,21). Then, TNF receptor-associated factor 6 (TRAF6), an ubiquitin E3 ligase, is recruited and NF-kB is activated, then proinflammatory cytokines are produced (Figure 1, priming step).…”

Section: Tlr4 Signaling Diverting Into the Myd88 Classic Nf-kb Activa...mentioning

confidence: 99%

IRF3 function and immunological gaps in sepsis

Basak,

Akashi-Takamura

2024

Front. Immunol.

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Lipopolysaccharide (LPS) induces potent cell activation via Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), often leading to septic death and cytokine storm. TLR4 signaling is diverted to the classical acute innate immune, inflammation-driving pathway in conjunction with the classical NF-κB pivot of MyD88, leading to epigenetic linkage shifts in nuclear pro-inflammatory transcription and chromatin structure-function; in addition, TLR4 signaling to the TIR domain-containing adapter-induced IFN-β (TRIF) apparatus and to nuclear pivots that signal the association of interferons alpha and beta (IFN-α and IFN-β) with acute inflammation, often coupled with oxidants favor inhibition or resistance to tissue injury. Although the immune response to LPS, which causes sepsis, has been clarified in this manner, there are still many current gaps in sepsis immunology to reduce mortality. Recently, selective agonists and inhibitors of LPS signals have been reported, and there are scattered reports on LPS tolerance and control of sepsis development. In particular, IRF3 signaling has been reported to be involved not only in sepsis but also in increased pathogen clearance associated with changes in the gut microbiota. Here, we summarize the LPS recognition system, main findings related to the IRF3, and finally immunological gaps in sepsis.

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MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis

Cited by 3 publications

References 46 publications

Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist

Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist

IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity in acute pancreatitis

IRF3 function and immunological gaps in sepsis

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