scholarly journals Leishmania donovani infection suppresses Allograft Inflammatory Factor-1 in monocytes and macrophages to inhibit inflammatory responses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ricardo Louzada da Silva ◽  
Diana M. Elizondo ◽  
Nailah Z. D. Brandy ◽  
Naomi L. Haddock ◽  
Thomas A. Boddie ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Inflammatory Cytokine ◽  
Leishmania Donovani ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Bone Marrow Cells ◽  
Parasitic Infections ◽  
Inflammatory Factor ◽  
Immune Functions ◽  
Inflammatory Cytokine Production

AbstractMacrophages and monocytes are important for clearance of Leishmania infections. However, immune evasion tactics employed by the parasite results in suppressed inflammatory responses, marked by deficient macrophage functions and increased accumulation of monocytes. This results in an ineffective ability to clear parasite loads. Allograft Inflammatory Factor-1 (AIF1) is expressed in myeloid cells and serves to promote immune responses. However, AIF1 involvement in monocyte and macrophage functions during parasitic infections has not been explored. This study now shows that Leishmania donovani inhibits AIF1 expression in macrophages to block pro-inflammatory responses. Mice challenged with the parasite had markedly reduced AIF1 expression in splenic macrophages. Follow-up studies using in vitro approaches confirmed that L. donovani infection in macrophages suppresses AIF1 expression, which correlated with reduction in pro-inflammatory cytokine production and increased parasite load. Ectopic overexpression of AIF1 in macrophages provided protection from infection, marked by robust pro-inflammatory cytokine production and efficient pathogen clearance. Further investigations found that inhibiting AIF1 expression in bone marrow cells or monocytes impaired differentiation into functional macrophages. Collectively, results show that AIF1 is a critical regulatory component governing monocyte and macrophage immune functions and that L. donovani infection can suppress the gene as an immune evasion tactic.

scholarly journals Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4430-4440 ◽  
Author(s):  
Thomas Duhen ◽  
Rebekka Duhen ◽  
Antonio Lanzavecchia ◽  
Federica Sallusto ◽  
Daniel J. Campbell
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Treg Cells ◽  
Receptor Expression ◽  
Inflammatory Cytokine Production ◽  
Th Cell ◽  
Different Types ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

Abstract FOXP3+ regulatory T (Treg) cells are a broadly acting and potent anti-inflammatory population of CD4+ T cells essential for maintaining immune homeostasis and preventing debilitating autoimmunity. Based on chemokine receptor expression, we identified distinct populations of Treg cells in human blood expected to colocalize with different Th cell subsets. Although each population was functionally suppressive, they displayed unique patterns of pro- and anti-inflammatory cytokine production, differentially expressed lineage-specifying transcription factors, and responded differently to antigens associated with Th1 and Th17 responses. These results highlight a previously unappreciated degree of phenotypic and functional diversity in human Treg cells that allows subsets with unique specificities and immunomodulatory functions to be targeted to defined immune environments during different types of inflammatory responses.

scholarly journals SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioanna Pantazi ◽  
Ahmed A. Al-Qahtani ◽  
Fatimah S Alhamlan ◽  
Hani Alothaid ◽  
Sabine Matou-Nasri ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Mrna Levels ◽  
Cytokine Storm ◽  
Inflammatory Cytokine Production ◽  
S Protein ◽  
Cytokines And Chemokines ◽  
Anti Inflammatory

The major cause of death in SARS-CoV-2 infected patients is due to de-regulation of the innate immune system and development of cytokine storm. SARS-CoV-2 infects multiple cell types in the lung, including macrophages, by engagement of its spike (S) protein on angiotensin converting enzyme 2 (ACE2) receptor. ACE2 receptor initiates signals in macrophages that modulate their activation, including production of cytokines and chemokines. IL-1R-associated kinase (IRAK)-M is a central regulator of inflammatory responses regulating the magnitude of TLR responsiveness. Aim of the work was to investigate whether SARS-CoV-2 S protein-initiated signals modulate pro-inflammatory cytokine production in macrophages. For this purpose, we treated PMA-differentiated THP-1 human macrophages with SARS-CoV-2 S protein and measured the induction of inflammatory mediators including IL6, TNFα, IL8, CXCL5, and MIP1a. The results showed that SARS-CoV-2 S protein induced IL6, MIP1a and TNFα mRNA expression, while it had no effect on IL8 and CXCL5 mRNA levels. We further examined whether SARS-CoV-2 S protein altered the responsiveness of macrophages to TLR signals. Treatment of LPS-activated macrophages with SARS-CoV-2 S protein augmented IL6 and MIP1a mRNA, an effect that was evident at the protein level only for IL6. Similarly, treatment of PAM3csk4 stimulated macrophages with SARS-CoV-2 S protein resulted in increased mRNA of IL6, while TNFα and MIP1a were unaffected. The results were confirmed in primary human peripheral monocytic cells (PBMCs) and isolated CD14+ monocytes. Macrophage responsiveness to TLR ligands is regulated by IRAK-M, an inactive IRAK kinase isoform. Indeed, we found that SARS-CoV-2 S protein suppressed IRAK-M mRNA and protein expression both in THP1 macrophages and primary human PBMCs and CD14+ monocytes. Engagement of SARS-CoV-2 S protein with ACE2 results in internalization of ACE2 and suppression of its activity. Activation of ACE2 has been previously shown to induce anti-inflammatory responses in macrophages. Treatment of macrophages with the ACE2 activator DIZE suppressed the pro-inflammatory action of SARS-CoV-2. Our results demonstrated that SARS-CoV-2/ACE2 interaction rendered macrophages hyper-responsive to TLR signals, suppressed IRAK-M and promoted pro-inflammatory cytokine expression. Thus, activation of ACE2 may be a potential anti-inflammatory therapeutic strategy to eliminate the development of cytokine storm observed in COVID-19 patients.

scholarly journals IRF5 Promotes Influenza Virus-Induced Inflammatory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models

2020 ◽  
Vol 94 (9) ◽  
Author(s):  
Jessica L. Forbester ◽  
Mathew Clement ◽  
Dannielle Wellington ◽  
Amy Yeung ◽  
Sandra Dimonte ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Inflammatory Cytokine Production ◽  
Induced Pluripotent

ABSTRACT Recognition of influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activate innate immune cells, and regulate adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate the mechanisms driving influenza virus-induced inflammation in humans. Interferon regulatory factor 5 (IRF5) is a transcription factor that plays important roles in the induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5−/− mice but not impacting type 1 interferon (IFN) production or virus replication. Using cytometry by time of flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in mediating human inflammatory responses by myeloid cells to IAV, we employed human-induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, demonstrating for the first time that induced pluripotent stem cell-derived dendritic cells (iPS-DCs) with biallelic mutations can be used to investigate the regulation of human virus-induced immune responses. Using this technology, we reveal that IRF5 deficiency in human DCs, or macrophages, corresponded with reduced virus-induced inflammatory cytokine production, with IRF5 acting downstream of Toll-like receptor 7 (TLR7) and, possibly, retinoic acid-inducible gene I (RIG-I) after viral sensing. Thus, IRF5 acts as a regulator of myeloid cell inflammatory cytokine production during IAV infection in mice and humans and drives immune-mediated viral pathogenesis independently of type 1 IFN and virus replication. IMPORTANCE The inflammatory response to influenza A virus (IAV) participates in infection control but contributes to disease severity. After viral detection, intracellular pathways are activated, initiating cytokine production, but these pathways are incompletely understood. We show that interferon regulatory factor 5 (IRF5) mediates IAV-induced inflammation and, in mice, drives pathology. This was independent of antiviral type 1 IFN and virus replication, implying that IRF5 could be specifically targeted to treat influenza virus-induced inflammation. We show for the first time that human iPSC technology can be exploited in genetic studies of virus-induced immune responses. Using this technology, we deleted IRF5 in human myeloid cells. These IRF5-deficient cells exhibited impaired influenza virus-induced cytokine production and revealed that IRF5 acts downstream of Toll-like receptor 7 and possibly retinoic acid-inducible gene I. Our data demonstrate the importance of IRF5 in influenza virus-induced inflammation, suggesting that genetic variation in the IRF5 gene may influence host susceptibility to viral diseases.

scholarly journals Entamoeba histolytica activation of caspase-1 degrades cullin that attenuates NF-κB dependent signaling from macrophages

2021 ◽  
Vol 17 (9) ◽  
pp. e1009936
Author(s):  
Attinder Chadha ◽  
France Moreau ◽  
Shanshan Wang ◽  
Antoine Dufour ◽  
Kris Chadee
Keyword(s):  
Entamoeba Histolytica ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Cysteine Proteinases ◽  
Inflammatory Cytokine Production ◽  
Downstream Signaling ◽  
Caspase 1 ◽  
Tnf Α ◽  
Cullin 4A

While Entamoeba histolytica (Eh)-induced pro-inflammatory responses are critical in disease pathogenesis, the downstream signaling pathways that subsequently dampens inflammation and the immune response remains unclear. Eh in contact with macrophages suppresses NF-κB signaling while favoring NLRP3-dependent pro-inflammatory cytokine production by an unknown mechanism. Cullin-1 and cullin-5 (cullin-1/5) assembled into a multi-subunit RING E3 ubiquitin ligase complex are substrates for neddylation that regulates the ubiquitination pathway important in NF-κB activity and pro-inflammatory cytokine production. In this study, we showed that upon live Eh contact with human macrophages, cullin-1/4A/4B/5 but not cullin-2/3, were degraded within 10 minutes. Similar degradation of cullin-1/5 were observed from colonic epithelial cells and proximal colonic loops tissues of mice inoculated with live Eh. Degradation of cullin-1/5 was dependent on Eh-induced activation of caspase-1 via the NLRP3 inflammasome. Unlike cullin-4B, the degradation of cullin-4A was partially dependent on caspase-1 and was inhibited with a pan caspase inhibitor. Cullin-1/5 degradation was dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4, but not EhCP-A5, based on pharmacological inhibition of the cysteine proteinases and EhCP-A5 deficient parasites. siRNA silencing of cullin-1/5 decreased the phosphorylation of pIκ-Bα in response to Eh and LPS stimulation and downregulated NF-κB-dependent TNF-α mRNA expression and TNF-α and MCP-1 pro-inflammatory cytokine production. These results unravel a unique outside-in strategy employed by Eh to attenuate NF-κB-dependent pro-inflammatory responses via NLRP3 activation of caspase-1 that degraded cullin-1/5 from macrophages.

Abstract 382: Lipin-1 Links Pro-inflammatory Responses and Foam Cell Formation by Oxidized-Low Density Lipoprotein-Elicited Macrophages

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aaron R Navratil ◽  
Aimee E Vozenilek ◽  
James A Cardelli ◽  
Jonette M Green ◽  
A W Orr ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Lipin 1

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and one of the underlying causes of cardiovascular disease (CVD). Macrophages participate decisively in the development and promotion of atherosclerosis. Macrophages infiltrate the arterial intima to ingest modified low density lipoproteins (e.g. oxLDLs) via scavenger receptors. The scavenging of oxLDLs results in foam cell formation due to enhanced lipid droplet biogenesis. These foam cells eventually release pro-inflammatory cytokines that promote atherosclerosis. However, it is currently unknown whether there is a link between lipid droplet biogenesis and pro-inflammatory cytokine production in macrophages that scavenge oxLDL. Lipin-1, a phosphatidate phosphohydrolase enzyme, partially contributes to macrophage pro-inflammatory cytokine production following stimulation with bacteria. Lipin-1 is also required for lipid droplet biogenesis in macrophages. Finally, we observed lipin-1 protein within macrophages from human atherosclerotic plaques. Thus, we hypothesized that lipid droplet biogenesis, via lipin-1 activity, directly contributes to foam cell pro-inflammatory cytokine production. To test this hypothesis we compared lipid droplet biogenesis and pro-inflammatory cytokine responses of oxLDL-stimulated wild type and lipin-1-depleted macrophages. Depletion of lipin-1 inhibited oxLDL-induced foam cell generation by reducing lipid droplet number, area, and staining intensity. There were no differences in scavenger receptor expression or uptake of oxLDL between wild type and lipin-1-depleted cells. In addition, depletion of lipin-1 also ablated oxLDL-elicited production of the pro-atherogenic cytokines tumor necrosis factor-α and interleukin-6. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to oxLDL. Furthermore, these data begin to link foam cell formation, via lipid droplet biogenesis, and pro-inflammatory cytokine production within oxLDL stimulated macrophages. Thus, our studies suggest that lipid droplet biogenesis may be an ideal therapeutic target to inhibit inflammation associated with atherosclerosis to treat CVD.

Ship Is Essential for Both Endotoxin- and CpG-Induced Tolerance and for Their Cross-Tolerance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3440-3440
Author(s):  
Laura M. Sly ◽  
Stephanie L. Omeis ◽  
Michael J. Rauh ◽  
Gerald Krystal
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Endotoxin Tolerance ◽  
Negative Regulator ◽  
In Vivo Studies ◽  
Initial Exposure ◽  
Inflammatory Cytokine Production ◽  
Induced Tolerance

Abstract An initial exposure to lipopolysaccharide (LPS, also known as endotoxin), which activates macrophages via Toll-like receptor 4 (TLR4), induces a transient state of hypo-responsiveness to a subsequent challenge with LPS. The mechanism underlying this phenomenon, termed endotoxin tolerance, remains poorly understood although the activation/upregulation of a number of negative regulators has been implicated. Related to this, we recently demonstrated that the SH2-containing inositol-5′-phosphatase, SHIP, which is a key negative regulator of the PI3K pathway in hematopoietic cells, is essential for endotoxin tolerance. Specifically, we found that SHIP−/− bone marrow derived macrophages (BMmΦs) do not display endotoxin tolerance. Moreover, an initial LPS treatment of wild-type BMmΦs increases the level of SHIP protein 10 fold and this increase is critical for the hypo-responsiveness to a subsequent LPS stimulation. Interestingly, this increase in SHIP protein is mediated by the LPS-induced production of autocrine-acting TGFβ and neutralizing antibodies to TGFβ, as well as antisense oligonucleotides to SHIP, block LPS-induced endotoxin tolerance. In vivo studies with SHIP+/+ and −/− mice confirm these in vitro findings and show a correlation between the duration of endotoxin tolerance and elevated SHIP levels (Sly et al., Immunity, in Press). We have now followed up on these studies by exploring the role of SHIP in the stimulation of other Toll-like receptors. Specifically, we asked whether SHIP plays a role in repressing CpG-induced pro-inflammatory cytokine production, which is mediated via the activation of TLR9. Our results, using SHIP+/+ and −/− BMmΦs, suggest that SHIP negatively regulates this TLR as well and is required for CpG-induced tolerance. Moreover, we found that CpG treated SHIP−/− BMmΦs show higher pro-inflammatory cytokine production compared to their SHIP+/+ counterparts when challenged with LPS. This indicates that SHIP plays a critical role in dampening down inflammatory responses in the innate immune system.

scholarly journals A15 MICROBES MEDIATE FIBER-INDUCED INFLAMMATION IN IBD

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 17-19
Author(s):  
H Armstrong ◽  
R Dickner ◽  
A Rieger ◽  
I K Mander ◽  
J Jerasi ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Receptor Expression ◽  
Dietary Fibers ◽  
Microbial Composition ◽  
Inflammatory Cytokine Production

Abstract Background The etiology of inflammatory bowel diseases (IBD) remains unknown, although gut microorganisms and diet have been implicated. Dietary fibers pass through the bowel undigested and are fermented within the intestine by microbes, promoting gut health. However, many IBD patients describe experiencing sensitivity to fibres. Interestingly, fiber receptors on immune cells are able to interact with fibers typically found on the surface of fungal cells (which share properties with dietary fibers), for example, resulting in a paradoxical pro-inflammatory response. Aims As an altered microbial composition is a hallmark of IBD, we hypothesized that the loss of fiber fermenting-microbes populating the IBD gut could lead to dietary fibers not being efficiently broken down into their beneficial biproducts, resulting in binding of intact fibers to pro-inflammatory host cell receptors. This can ultimately drive pro-inflammatory responses and a microenvironment that promotes continued dysbiosis and increased pathogenicity of select microbes, as observed in IBD. Methods Fiber receptor expression gut was examined using immunohistochemistry and flow cytometry and demonstrated elevated receptor expression due to increased presence of immune cells in IBD patient biopsies. Cytokine secretion, in response to fiber (5mg/mL) or pre-fermented fibers, cultured with microbes of interest, was measured by ELISAs in cell lines in vitro and biopsy tissues cultured ex vivo. Results Whole-fibers induced pro-inflammatory cytokine production in macrophage, monocytes, and neutrophils. Specific microbes were capable of fermenting fiber, measured by gas chromatography. Pre-fermentation of fibers by these microbes reduced inflammatory cytokine production. The fiber oligofructose increased IL-1β in pediatric CD (n=44) and UC (n=29) biopsies cultured ex vivo but not in non-IBD (n=25). The increase was greater in patients with more severe disease. Pre-fermentation of oligofructose by bacteria reduced this secretion of IL-1β. Whole-microbe intestinal washes from severe IBD patients were unable to ferment oligofructose or reduce fiber-associated inflammation in macrophage cells compared to remission or non-IBD children. Statistical analysis of food frequency questionnaire (FFQ) data on fiber consumption demonstrated that fiber-associated inflammation in patient biopsies cultured ex vivo (ELISA and qPCR) correlated with fiber avoidance (FFQ). Conclusions Comparing in vitro findings to our patient FFQs, intestinal washes (microbe abundance), and detailed patient history will better define the relationship between microbes, dietary fibers, and gut inflammation in IBD. This will allow for tailored dietary intervention through dietary recommendations, prebiotic, and/or probiotic therapies. Funding Agencies CCCWeston Foundation, WCHRI

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