chemokine production
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2022 ◽  
Vol 18 (1) ◽  
pp. e1010200
Aparna Jorapur ◽  
Lisa A. Marshall ◽  
Scott Jacobson ◽  
Mengshu Xu ◽  
Sachie Marubayashi ◽  

The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.

Weihong Wang ◽  
Joshua S. Prokopec ◽  
Yixin Zhang ◽  
Maria Sukhoplyasova ◽  
Himaly Shinglot ◽  

2021 ◽  
Vol 12 ◽  
Joshua Oluoch Amimo ◽  
Sergei Alekseevich Raev ◽  
Juliet Chepngeno ◽  
Alfred Omwando Mainga ◽  
Yusheng Guo ◽  

Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260447
Kiwako Yamamoto-Hanada ◽  
Yuichi Suzuki ◽  
Limin Yang ◽  
Mayako Saito-Abe ◽  
Miori Sato ◽  

Skin inflammation leads to altered cytokine/chemokine production and causes systemic inflammation. The systemic mechanism of atopic dermatitis (AD) is recognized to affect systemic metabolism. This study aimed to examine the relationship between early-onset persistent eczema and body weight, height, and body mass index (BMI), in addition to food allergy in a birth cohort among infants. This study design was a nationwide, multicenter, prospective birth cohort study—the Japan Environment and Children’s Study (JECS). Generalized linear models were fitted for z scores of weight, height, BMI, and food allergy to evaluate the relationship between eczema and these outcomes for infants at age1, 2, and 3 years. Persistent eczema was negatively associated with height at the age of 2 years (estimated coefficient, −0.127; 95% confidence interval [CI], −0.16 to −0.095) and 3 years (−0.177; 95% CI, −0.214 to −0.139). The same tendency was also observed with weight and BMI. Early disease onset at younger than 1 year and persistent eczema had the strongest association with development of food allergy at age 3 years (OR, 11.794; 95% CI, 10.721–12.975). One phenotype of eczema with early-onset and persistent disease creates a risk of both physical growth impairment and development of food allergy. Infants who present with the early-onset and persistent type of eczema should be carefully evaluated daily for impaired physical growth and development of food allergy.

2021 ◽  
Vol 22 (23) ◽  
pp. 12923
Zhiyi Ding ◽  
Feifei Du ◽  
Richard Garland Averitt V ◽  
Gabriel Jakobsson ◽  
Carl-Fredrik Rönnow ◽  

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1778
Yi-Shin Wu ◽  
Chian-Ruei Chen ◽  
Yun-Ting Yeh ◽  
Han-Huei Lin ◽  
Yin-Hsuan Peng ◽  

Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In this study, the effects of DMGF on the cytokine production and cell migration of inflammatory macrophages were investigated. The inhibition of cytokine and chemokine production by DMGF in LPS-treated macrophages was analyzed by a multiplex cytokine assay. Then, the integrin molecules used for cell adhesion and regulators of actin polymerization were observed by RT-PCR and recorded using confocal imaging. The DMGF interaction with estrogen receptor α (ERα) was modeled structurally by molecular docking and validated by an ERα reporter assay. DMGF inhibited TNF-α, IL-1β, and IL-6 production in LPS-induced macrophages. DMGF also inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac1 pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity. These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling.

2021 ◽  
Vol 11 (1) ◽  
A. R. da Silva Ferreira ◽  
S. A. J. van der Aa ◽  
T. Wehkamp ◽  
H. R. Wardill ◽  
J. P. ten Klooster ◽  

AbstractGastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005–50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

2021 ◽  
Kathryn Hally

<p>Platelet activation is pathological in acute myocardial infarction (AMI). Despite treatment with dual anti-platelet therapy (DAPT), platelet activation can continue to occur post-AMI and has been linked to an increased risk of recurrent cardiovascular events. Toll-like receptors (TLRs) are important innate immune receptors, and platelets are known to express a subset of TLRs. The functional significance of these platelet-TLR pathways in AMI has not been fully examined but may contribute to persistent post-AMI platelet activation. Platelet-TLR expression, TLR-mediated platelet activation and the platelet effect on leukocyte responses to TLR stimulation were examined in this thesis.   Platelet-TLR expression and TLR-mediated platelet activation was examined for a subset of these receptors (TLR1, 2, 4, 6 and 9) in healthy subjects and in AMI subjects on DAPT. We observed an increase in platelet expression of TLR1, 4 and 9 in AMI platelets compared to healthy subjects. Further investigation into platelet-TLR9 expression showed an increase in expression upon platelet activation in healthy, but not AMI, subjects. We observed direct, dose-dependent platelet activation in response to Pam3CSK4 (TLR2/1 agonist) and ODN2009 (TLR9 agonist) in healthy subjects and in AMI on DAPT. For both cohorts, platelets were also directly activated by a high dose of LPS (TLR4 agonist) but were not directly activated by FSL-1 (TLR6 agonist). These results demonstrate that some (TLR1, 2, 4 and 9), but not other (TLR6), platelet-TLR pathways can cause platelet activation in AMI despite treatment with potent anti-platelet therapy.   For the results described above, we were unable to assess TLR-mediated platelet activation in the absence of anti-platelet therapy in AMI subjects as these drugs are administered before or immediately upon presentation to hospital. It was therefore not possible to exclude the possibility that DAPT was providing a degree of inhibition of platelet activation in AMI patients. To address this, we determined the extent to which aspirin monotherapy or DAPT could inhibit platelet activation in response to TLR2/1, TLR4 and TLR9 stimulation in a cross-over study in healthy subjects. We demonstrated that DAPT only modestly inhibited, and aspirin monotherapy did not inhibit, platelet activation in response to all TLR agonists tested and platelets still became potently activated despite treatment with anti-platelet agents. These platelet-TLRs represent intact on-treatment platelet activation pathways.   Lastly, we determined the extent to which platelets modulate leukocyte responses to TLR2/1, TLR2/6 and TLR4 stimulation. Platelets were able to reduce neutrophil responses to TLR stimulation, and modulated PBMC cytokine and chemokine production in a complex manner following stimulation with LPS and FSL-1. The presence of platelets did not change cytokine/chemokine production in response to Pam3CSK4, demonstrating a TLR agonist-specific manner of platelet modulation. We further investigated the effect of platelets on neutrophil responses to TLR stimulation. With platelets, neutrophil activation was attenuated, and phagocytic activity was increased in unstimulated cultures and in response to various doses of Pam3CSK4 and FSL-1. Neutrophil elastase secretion was attenuated in unstimulated cultures and in response to low-dose stimulation with all three TLR agonists. We show that platelets can both augment and attenuate various markers of neutrophil function.  Together, this work indicates that platelets express functional TLR pathways that can differentially regulate a number of thrombotic and inflammatory responses in healthy subjects and in subjects with AMI.</p>

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