Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease

Boaru, Sorina Georgiana; Borkham-Kamphorst, Erawan; Tihaa, Lidia; Haas, Ute; Weiskirchen, Ralf

doi:10.1186/1476-9255-9-49

Cited by 125 publications

(105 citation statements)

References 39 publications

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“…Kupffer cells are a major source of IL-1β [38], thereby indicating the importance of inflammasomes in initiating the pro-inflammatory response. High expression of inflammasome components in fibrotic lesions was found using animal models involving CCl 4 treatment or bile duct ligation [33]. …”

Section: Inflammatory Bed Inflammasomes and Regenerating Nodules Durmentioning

confidence: 99%

See 1 more Smart Citation

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna¹,

Rastogi²,

Trehanpati³

et al. 2013

Liver Cancer

182

121

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Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the “inflammasome” (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

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Section: Inflammatory Bed Inflammasomes and Regenerating Nodules Durmentioning

confidence: 99%

“…3). Inflammasome activation, in turn, is responsible for local and systemic inflammatory reactions, recruitment of neutrophils and platelets and activation of the innate immune system [32,33]. …”

Section: Inflammatory Bed Inflammasomes and Regenerating Nodules Durmentioning

confidence: 99%

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna¹,

Rastogi²,

Trehanpati³

et al. 2013

Liver Cancer

182

121

View full text Add to dashboard Cite

show abstract

“…Thus, AIM2 is also treated as one of the cytosolic DNA sensors [15]. Previous study found that AIM2 was prominently expressed in Kupffer cells in many animal models of hepatitis [16]. Recently Wu's group indicated that there might be a relationship between AIM2 expression in peripheral blood mononuclear cells and human with acute and chronic hepatitis B.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 Acts as an Important Regulator to Kupffer Cells Activation at the Early Stage of Con A-Induced Acute Liver Failure via AIM2 Signaling Pathway

Yang

Lou

Zhou

et al. 2014

Cell Physiol Biochem

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Background: Acute liver failure (ALF), known as a rapid and severe clinical syndrome, can induce multiple organ dysfunction and failure. It was noticed that Kupffer cells activation at the initial phase was involved in some intense inflammatory responses in the pathogenesis of ALF. However, detailed regulation mechanism of Kupffer cells activation during ALF is still obscured. Present study aimed to discover the potential regulator and explore deeper information of Kupffer cells activation at the early stage of ALF. Methods: The mouse model of ALF was established by Concanavalin A injection. Dynamic immunological statuses of Kupffer cells at the early stage of ALF were exhibited by detecting typical cytokines. The expression of inflammasome AIM2 was measured in both RNA and protein level. Its role of affecting Kupffer cells activation during ALF by inducing IL-1β production was identified by RNA interference in vitro. Moreover, the expression of miR-223 in vivo was measured by q-PCR and its role in regulating Kupffer cells activation during Con A induced ALF was determined by RNAs transfection. Results: Present study showed that mass production of IL-1β from isolated Kupffer cells in Con A treated mice might be the main driving force of Kupffer cells pro-inflammatory activation during ALF. The role of AIM2 in affecting pro-inflammatory activation of Kupffer cells by inducing IL-1β production was crucial to ALF. Further study found that miR-223 acted as a regulator in Kupffer cells activation at the early stage of ALF by influencing IL-1β production via AIM2 pathway. Conclusion: For the first time, this paper demonstrated that miR-223 acted to inhibit IL-1β production via AIM2 pathway, suppressing Kupffer cells pro-inflammatory activation at the early stage of ALF. Thus, it played an important role in the pathogenesis of ALF.

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“…Each of these inflammasomes consists of a sensor NLR molecule, which is the adapter protein known as apoptosis-associated speck-like protein containing CARD (ASC) and the inflammatory protease caspase-1 enzyme (90). The latest findings from experimental models of inflammatory and fibrotic liver disease on expression analysis of inflammasomes showed that there is a possibility of co-expression of multiple inflammasomes within the same cell type in the inflamed tissue, indicating the requirement of co-factors for inflammasome activation (86).…”

Section: Activation Of Inflammasomesmentioning

confidence: 99%

“…The caspase 1-mediated activation of IL-1β cytokine family ultimately leads to recruitment and activation of immune cells such as neutrophils and platelets at the site of tissue injury/infection (91). The active caspase-1 could also cause a rapid, pro-inflammatory form of cell death known as pyroptosis (86). An excessive caspase 1-mediated release of pro-inflammatory cytokines and pyroptosis due to uncontrolled activation of inflammasomes could further exacerbate the tissue damage or worsen the infection in the host; therefore, a fine balance between the activation and inhibition of inflammation is necessary to guard the cytosolic sanctity (87).…”

Section: Formation Of Inflammasomes Is Initiated Upon Recognition Ofmentioning

confidence: 99%

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

Rahiman¹,

Sarah²

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Inflammation is a complex physiological process that involves host defense mechanisms in response to the intrusion of harmful external stimuli. Uncoordinated inflammatory responses, however, are the underlying pathophysiological cause of many chronic diseases. Inflammation is characterised by the burgeoning migration of leukocytes to the point of injury and subsequent release of pro-nociceptive mediators, generating inflammatory pain. Dynorphin 1-17 (DYN 1-17) is endogenously produced and released from leukocytes upon stimulation by local inflammatory factors in the inflamed area. This opioid peptide primarily binds to kappa-opioid receptor (KOR) to produce analgesia. Under inflammatory milieu, DYN 1-17 undergoes spontaneous degradation, yielding a variety of opioid and non-opioid fragments that may have significant implications in inflammation. The underlying cellular effects of these fragments remain unclear. This thesis seeks to explore potential mechanistic insights into selected major DYN 1-17 fragments, identified from a previous biotransformation study of DYN 1-17 in rodent inflamed tissue. This thesis examines the DYN 1-17 fragments modulation of intracellular signals associated with inflammation and thereby, gain an insight into novel therapeutic targets through exploring these endogenous mechanisms.Utilising THP-1 macrophages as an in vitro model of inflammation, this thesis begins with a semiquantitative assessment of nuclear factor-kappa B/p65 (NF-κB/p65) translocation, a major transcription factor that regulates genes responsible for immune and inflammatory responses. The findings presented in Chapter Three of this thesis demonstrated that DYN 1-17 and selected major fragments (DYN 1-6, 1-7, 1-9, 1-10, 1-11, 3-14, 6-12, 2-17 and 7-17) significantly attenuated NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS), with the greatest reduction observed with DYN 1-7 at 10 nM. A selective KOR antagonist, ML-190, was used to examine KOR involvement in this inhibitory action. ML-190 significantly reversed the inhibition of NF-κB/p65 translocation produced by DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not DYN 1-10 and DYN 1-11.Cytokine production is linked as a downstream process to NF-κB activation; hence it is necessary to evaluate the ability of DYN 1-17 and selected biotransformation fragments in the modulation of IL-1β and TNF-α release in differentiated THP-1 cells, as presented in Chapter Four, to gain an insight into the effects on major pro-inflammatory cytokines. DYN 1-17 and the fragments, demonstrated differential modulatory effects on LPS-induced release of IL-1β and TNF-α. DYN 1-7 and DYN 1-6, inhibited and elevated the secretion of both cytokines, respectively, in a concentration-dependent manner (10 -11 to 10 -7 M). DYN 1-17, however, only inhibited IL-1β release from differentiated iii THP-1 cells and had no effect on TNF-α secretion. Intriguingly, DYN 3-14 at 10 -17 to 10 -11 M demonstrated significant inhibition on IL-1β release and paradoxically increased TNF-α lev...

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Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease

Cited by 125 publications

References 39 publications

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

MicroRNA-223 Acts as an Important Regulator to Kupffer Cells Activation at the Early Stage of Con A-Induced Acute Liver Failure via AIM2 Signaling Pathway

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

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