Altered cleavage of Caspase-1 in hepatocytes limits control of malaria in the liver

AbstractMalaria, caused by Plasmodium parasites, is a devastating disease that kills over half a million people each year1. Plasmodium sporozoites inoculated by mosquitoes into mammalian hosts undergo a clinically silent phase of obligatory development and replication in hepatocytes before initiating the life-threatening blood-stage of malaria2. Thus, understanding the immune responses elicited by Plasmodium infection in the liver is key to controlling clinical malaria and transmission3,4. Here, we show that Plasmodium DNA can be detected by AIM2 (absent in melanoma 2) sensors in the infected hepatocytes, resulting in Caspase-1 activation and pyroptotic cell-death. However, Caspase-1 was observed to undergo only partial cleavage in hepatocytes, limiting pyroptosis, and the maturation of pro-inflammatory cytokines classically associated with Caspase-1 activation. We discovered that the extent of Caspase-1 cleavage in cells is determined by the expression of ASC (apoptosis-associated speck-like protein containing a CARD). ASC expression is inherently low in hepatocytes, and transgenically enhancing it in the hepatocytes induced complete processing of Caspase-1, efficient secretion of pro-inflammatory cytokines, enhanced pyroptotic cell-death, and markedly improved control of malaria infection in the liver. In addition to describing a novel pathway of natural immunity to malaria, our findings uncover a key aspect of liver biology that may have been exploited during evolution by successful hepatotropic pathogens.

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Inflammasomes and viruses: cellular defence versus viral offence

Journal of General Virology ◽

10.1099/vir.0.042978-0 ◽

2012 ◽

Vol 93 (10) ◽

pp. 2063-2075 ◽

Cited By ~ 40

Author(s):

Anna M. Gram ◽

Joost Frenkel ◽

Maaike E. Ressing

Keyword(s):

Immune Responses ◽

Viral Infection ◽

Inflammatory Cytokines ◽

Caspase 1 ◽

Multimeric Complex ◽

Long Time ◽

Cellular Defence ◽

Pro Inflammatory Cytokines

Pro-inflammatory cytokines are important mediators in immune responses against invading pathogens, including viruses. Precursors of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 are processed by caspase-1. Caspase-1 is activated through autocleavage, but how this is regulated remained elusive for a long time. In 2002, an intracellular multimeric complex was discovered that facilitated caspase-1 cleavage and was termed ‘inflammasome’. To date, different inflammasomes have been described, which recognize a variety of ligands and pathogens. In this review, we discuss the role of inflammasomes in sensing viral infection as well as the evasion strategies that viruses developed to circumvent inflammasome-dependent effects.

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Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

PLoS ONE ◽

10.1371/journal.pone.0022485 ◽

2011 ◽

Vol 6 (7) ◽

pp. e22485 ◽

Cited By ~ 48

Author(s):

J. Jason Collier ◽

Susan J. Burke ◽

Mary E. Eisenhauer ◽

Danhong Lu ◽

Renee C. Sapp ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Cytokines ◽

Pancreatic Β Cell ◽

Β Cell ◽

Pro Inflammatory Cytokines

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Host F-box protein 22 enhances the uptake of Brucella by macrophages and drives a sustained release of pro-inflammatory cytokines through degradation of the anti-inflammatory effector proteins of Brucella.

10.1101/2021.03.15.435452 ◽

2021 ◽

Author(s):

Girish Radhakrishnan ◽

Varadendra Mazumdar ◽

Kiranmai Joshi ◽

Binita Roy Nandi ◽

Swapna Namani ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Cytokines ◽

Effector Proteins ◽

Host Protein ◽

Limited Information ◽

Phagocytic Cells ◽

Scf Complex ◽

Enhanced Production ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Brucella species are intracellular bacterial pathogens, causing the world-wide zoonotic disease, brucellosis. Brucella invade professional and non-professional phagocytic cells, followed by resisting intracellular killing and establishing a replication permissive niche. Brucella also modulate the innate and adaptive immune responses of the host for their chronic persistence. The complex intracellular cycle of Brucella majorly depends on multiple host factors but limited information is available on host and bacterial proteins that play essential role in the invasion, intracellular replication and modulation of host immune responses. By employing an siRNA screening, we identified a role for the host protein, FBXO22 in Brucella -macrophage interaction. FBXO22 is the key element in the SCF E3 ubiquitination complex where it determines the substrate specificity for ubiquitination and degradation of various host proteins. Downregulation of FBXO22 by siRNA or CRISPR-Cas9 system, resulted diminished uptake of Brucella into macrophages, which was dependent on NF-κB-mediated regulation of phagocytic receptors. FBXO22 expression was upregulated in Brucella -infected macrophages that resulted induction of phagocytic receptors and enhanced production of pro-inflammatory cytokines through NF-κB. Furthermore, we found that FBXO22 recruits the effector proteins of Brucella , including the anti-inflammatory proteins, TcpB and OMP25 for degradation through the SCF complex. We did not observe any role for another F-box containing protein of SCF complex, β-TrCP in Brucella -macrophage interaction. Our findings unravel novel functions of FBXO22 in host-pathogen interaction and its contribution to pathogenesis of infectious diseases.

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Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina

The Journal of Pathology ◽

10.1002/path.2858 ◽

2011 ◽

Vol 224 (2) ◽

pp. 245-260 ◽

Cited By ~ 73

Author(s):

Viswanathan Sivakumar ◽

Wallace S Foulds ◽

Chi D Luu ◽

Eng-Ang Ling ◽

Charanjit Kaur

Keyword(s):

Cell Death ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Inflammatory Cytokines ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death ◽

Pro Inflammatory Cytokines

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Polyamine Transport Protein PotD Protects Mice against Haemophilus parasuis and Elevates the Secretion of Pro-Inflammatory Cytokines of Macrophage via JNK–MAPK and NF–κB Signal Pathways through TLR4

Vaccines ◽

10.3390/vaccines7040216 ◽

2019 ◽

Vol 7 (4) ◽

pp. 216 ◽

Cited By ~ 1

Author(s):

Ke Dai ◽

Xiaoyu Ma ◽

Zhen Yang ◽

Yung-Fu Chang ◽

Sanjie Cao ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Cytokines ◽

Transport System ◽

Signal Pathways ◽

Raw 264.7 ◽

Raw 264.7 Macrophages ◽

Cellular Immune Responses ◽

Polyamine Transport ◽

Cellular Immune ◽

Pro Inflammatory Cytokines

The potD gene, belonging to the well-conserved ABC (ATP-binding cassette) transport system potABCD, encodes the bacterial substrate-binding subunit of the polyamine transport system. In this study, we found PotD in Haemophilus (Glaesserella) parasuis could actively stimulate both humoral immune and cellular immune responses and elevate lymphocyte proliferation, thus eliciting a Th1-type immune response in a murine immunity and infection model. Stimulation of Raw 264.7 macrophages with PotD validated that Toll-like receptor 4, rather than 2, participated in the positive transcription and expression of pro-inflammatory cytokines IL–1β, IL–6, and TNF–α using qPCR and ELISA. Blocking signal-regulated JNK–MAPK and RelA(p65) pathways significantly decreased PotD-induced pro-inflammatory cytokine production. Overall, we conclude that vaccination of PotD could induce both humoral and cellular immune responses and provide immunoprotection against H. parasuis challenge. The data also suggest that Glaesserella PotD is a novel pro-inflammatory mediator and induces TLR4-dependent pro-inflammatory activity in Raw 264.7 macrophages through JNK–MAPK and RelA(p65) pathways.

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UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells

Journal of Endocrinology ◽

10.1677/joe-09-0356 ◽

2010 ◽

Vol 206 (2) ◽

pp. 183-193 ◽

Cited By ~ 19

Author(s):

José Edgar Nicoletti-Carvalho ◽

Tatiane C Araújo Nogueira ◽

Renata Gorjão ◽

Carla Rodrigues Bromati ◽

Tatiana S Yamanaka ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Cytokines ◽

Interleukin 6 ◽

Common Mechanism ◽

Rinm5f Cells ◽

Β Cell ◽

Induced Apoptosis ◽

Unconditional Stimulation ◽

Stimulation Of ◽

Pro Inflammatory Cytokines

Unfolded protein response (UPR)-mediated pancreatic β-cell death has been described as a common mechanism by which palmitate (PA) and pro-inflammatory cytokines contribute to the development of diabetes. There are evidences that interleukin 6 (IL6) has a protective action against β-cell death induced by pro-inflammatory cytokines; the effects of IL6 on PA-induced apoptosis have not been investigated yet. In the present study, we have demonstrated that PA selectively disrupts IL6-induced RAC-alpha serine/threonine-protein kinase (AKT) activation without interfering with signal transducer and activator of transcription 3 phosphorylation in RINm5F cells. The inability of IL6 to activate AKT in the presence of PA correlated with an inefficient protection against PA-induced apoptosis. In contrast to PA, IL6 efficiently reduced apoptosis induced by pro-inflammatory cytokines. In addition, we have demonstrated that IL6 is unable to overcome PA-stimulated UPR, as assessed by activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, X-box binding protein-1 gene mRNA splicing, and pancreatic eukaryotic initiation factor-2α kinase phosphorylation, whereas no significant induction of UPR by pro-inflammatory cytokines was detected. This unconditional stimulation of UPR and apoptosis by PA was accompanied by the stimulation of CHOP and tribble3 (TRIB3) expression, irrespective of the presence of IL6. These findings suggest that IL6 is unable to protect pancreatic β-cells from PA-induced apoptosis because it does not repress UPR activation. In this way, CHOP and ATF4 might mediate PA-induced TRIB3 expression and, by extension, the suppression of IL6 activation of pro-survival kinase AKT.

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The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses

10.1101/404384 ◽

2018 ◽

Author(s):

Lindsay Broadbent ◽

Jonathon D. Coey ◽

Michael D. Shields ◽

Ultan F. Power

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Virus Replication ◽

Growth Kinetics ◽

Rsv Infection ◽

Syncytial Virus ◽

Pro Inflammatory Cytokines

AbstractRespiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-λ1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-λ1 production. However, the role of TLR4 in RSV infection and concomitant IFN-λ1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-λ1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-λ1 secretion, while JSH-23, an NF-κB inhibitor, reduced IFN-λ1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-λ1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- κB and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.ImportanceThe role of TLR4 in RSV infection and IFN-λ1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-λ1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.

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Pro- and anti-inflammatory immune response profiling prevents severe malaria among Nigerians infected with Plasmodium falciparum: the future for malaria vaccines and therapeutics.

10.21203/rs.2.22063/v1 ◽

2020 ◽

Author(s):

DANIEL OSAGIE OKPOKOR ◽

ASAGA MAC PETER ◽

Ajibaye Olusola ◽

Anthony Danaan Dakul

Keyword(s):

Plasmodium Falciparum ◽

Immune Responses ◽

Severe Malaria ◽

Inflammatory Cytokines ◽

Parasite Density ◽

Malaria Parasite ◽

World Health ◽

Tnf Α ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background Available evidence indicates that the various stages of the malaria parasite life cycle have specific immune responses. The pro-inflammatory cytokines tend to play an important role in preventing malaria and killing the parasites. Furthermore, the relative levels of pro-and anti-inflammatory cytokines are essential mediators of malaria anemia production and outcomes. Natural human immune responses to malaria recognize extracellular sporozoites and merozoites, both of which have surface-exposed antigens, and which are currently being developed for various vaccines. Methods A total of four hundred sixty- two (462) participants were tested for Plasmodium falciparum. The procedure employed were parasite staining using World Health Organization parasitology laboratory protocol [Microscopy] of Giemsa staining and Enzyme linked immunosorbent assay [ELISA]. Results The subjects in this study showed high levels of INF-γ and TNF-α which decreases with increased malaria severity and high parasite density. These results suggest that INF-γ cytokine and TNF-α may contribute to protection against severe malaria anaemia and parasite clearance. Conversely, infected participants showed higher levels of IL-10, which decreases with severe malaria parasite, furthermore IL-10 levels correlated with parasite density. These findings suggest that higher levels of anti-inflammatory cytokines, especially IL-10 levels may contribute to pathogenesis of complicated malaria by inhibiting the INF-γ and TNF-α production. Conclusion Molecular biological and other serological analysis are needed to elucidate the implication of these cytokines and other pro-inflammatory cytokines as IL-17, IL-21 and IL-22 in the responses to malaria and consequently their involvement in malaria vaccine construct/development as well as other therapeutics for the treatment and elimination of the malaria parasite in our environment.

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