scholarly journals GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease

2016 ◽  
Vol 213 (10) ◽  
pp. 1983-1998 ◽  
Author(s):  
Angus T. Stock ◽  
Jacinta A. Hansen ◽  
Matthew A. Sleeman ◽  
Brent S. McKenzie ◽  
Ian P. Wicks
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Immune Cell ◽  
Cardiac Fibroblasts ◽  
Developed Countries ◽  
Water Soluble ◽  
Cardiac Inflammation ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Macrophage Colony

Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD.

Toll-like receptors stimulate human neutrophil function

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2660-2669 ◽  
Author(s):  
Fumitaka Hayashi ◽  
Terry K. Means ◽  
Andrew D. Luster
Keyword(s):  
Immune Cell ◽  
Germ Line ◽  
Quantitative Polymerase Chain Reaction ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Toll Like Receptors ◽  
Gm Csf ◽  
Latex Beads ◽  
Macrophage Colony ◽  
And Function

Abstract The first immune cell to arrive at the site of infection is the neutrophil. Upon arrival, neutrophils quickly initiate microbicidal functions, including the production of antimicrobial products and proinflammatory cytokines that serve to contain infection. This allows the acquired immune system enough time to generate sterilizing immunity and memory. Neutrophils detect the presence of a pathogen through germ line-encoded receptors that recognize microbe-associated molecular patterns. In vertebrates, the best characterized of these receptors are Toll-like receptors (TLRs). We have determined the expression and function of TLRs in freshly isolated human neutrophils. Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10—all the TLRs except TLR3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels. The agonists of all TLRs expressed in neutrophils triggered or primed cytokine release, superoxide generation, and L-selectin shedding, while inhibiting chemotaxis to interleukin-8 (IL-8) and increasing phagocytosis of opsonized latex beads. The response to the TLR9 agonist nonmethylated CpG-motif-containing DNA (CpG DNA) required GM-CSF pretreatment, which also enhanced the response to the other TLR agonists. Finally, using quantitative polymerase chain reaction (QPCR), we demonstrate a chemokine expression profile that suggests that TLR-stimulated neutrophils recruit innate, but not acquired, immune cells to sites of infection. (Blood. 2003;102:2660-2669)

Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor α-independent mouse model

2008 ◽  
Vol 68 (5) ◽  
pp. 721-728 ◽  
Author(s):  
C Plater-Zyberk ◽  
L A B Joosten ◽  
M M A Helsen ◽  
M I Koenders ◽  
P A Baeuerle ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Colony Stimulating Factor ◽  
Streptococcal Cell Wall ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Objective:A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis (RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy.Methods:A chronic relapsing arthritis was induced in C57Bl/6 wild type (WT) and C57Bl/6 genetically deficient for IL17 receptor (IL17R knockout (KO)) mice by intra-articular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments (intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators.Results:Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)α blockade had essentially no effect.Conclusion:Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNFα antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFα inhibitors.

Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Robin Kate Kelley ◽  
Emily Mitchell ◽  
Spencer Behr ◽  
Jimmy Hwang ◽  
Bridget Keenan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stage 1

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.

scholarly journals Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC

2018 ◽  
Vol 1 (6) ◽  
pp. e201800093 ◽  
Author(s):  
Stefan Schierer ◽  
Christian Ostalecki ◽  
Elisabeth Zinser ◽  
Ricarda Lamprecht ◽  
Bianca Plosnita ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Extracellular Vesicles ◽  
Immune Reaction ◽  
Immune Cell ◽  
Mouse Skin ◽  
Inflammatory Cells ◽  
Activation Markers ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Maturation Stimulus

During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell–activating and IL-12p70–secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation.

scholarly journals Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells

2011 ◽  
Vol 301 (2) ◽  
pp. C530-C539 ◽  
Author(s):  
Michael Romio ◽  
Benjamin Reinbeck ◽  
Sabine Bongardt ◽  
Sandra Hüls ◽  
Sandra Burghoff ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokines ◽  
Wild Type ◽  
Murine Splenocytes ◽  
Gm Csf ◽  
A2a Receptors ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Ifn Γ ◽  
Macrophage Colony

CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4+ T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73−/− T cells (wild type: 4.36 ± 0.21; CD73−/−: 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4+ T-cells. Treatment of stimulated CD4+ T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4+ T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.

scholarly journals The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes

2017 ◽  
Vol 214 (11) ◽  
pp. 3293-3310 ◽  
Author(s):  
Atsushi Anzai ◽  
Jennifer L. Choi ◽  
Shun He ◽  
Ashley M. Fenn ◽  
Manfred Nairz ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Potential Therapeutic Target ◽  
Gm Csf ◽  
Left Ventricular Rupture ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor ◽  
Human And Mouse

Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti–GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.

scholarly journals Granulocyte Macrophage Colony-Stimulating Factor

2001 ◽  
Vol 194 (7) ◽  
pp. 873-882 ◽  
Author(s):  
Jonathan L. McQualter ◽  
Rima Darwiche ◽  
Christine Ewing ◽  
Manabu Onuki ◽  
Thomas W. Kay ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Specific Antigen ◽  
Demyelinating Diseases ◽  
Colony Stimulating Factor ◽  
Cns Inflammation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF−/− mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis.

scholarly journals IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Chang Jia ◽  
Yingzhi Zhuge ◽  
Shuchi Zhang ◽  
Chao Ni ◽  
Linlin Wang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Kawasaki Disease ◽  
Mouse Model ◽  
Cell Apoptosis ◽  
Developed Countries ◽  
Protective Role ◽  
Potential Candidate ◽  
Endothelial Cell Apoptosis ◽  
Apoptosis And Inflammation

AbstractKawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.

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