scholarly journals MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Stefanie Riesenberg ◽  
Angela Groetchen ◽  
Robert Siddaway ◽  
Tobias Bald ◽  
Julia Reinhardt ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Myeloid Cell ◽  
Cell Recruitment ◽  
Cytokine Responsiveness

scholarly journals Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans

2020 ◽  
Vol 41 (31) ◽  
pp. 2938-2948
Author(s):  
Annelie Shami ◽  
Dorothee Atzler ◽  
Laura A Bosmans ◽  
Holger Winkels ◽  
Svenja Meiler ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Myeloid Cell ◽  
Tumour Necrosis Factor Receptor ◽  
Cell Recruitment ◽  
Atherosclerosis Progression ◽  
Fibrous Cap ◽  
Plaque Area ◽  
Asymptomatic Patients ◽  
Cerebrovascular Events ◽  
Plaque Phenotype

Abstract Aims GITR—a co-stimulatory immune checkpoint protein—is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD). Methods and results GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr−/−Apoe−/− mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr−/−Apoe−/− and Apoe−/− monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr−/−Apoe−/− monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity. Conclusion Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.

Heterogeneity of human prostate carcinoma‐associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment

The Prostate ◽  
2019 ◽  
Vol 80 (2) ◽  
pp. 173-185 ◽  
Author(s):  
Renee E. Vickman ◽  
Meaghan M. Broman ◽  
Nadia A. Lanman ◽  
Omar E. Franco ◽  
Putu Ayu G. Sudyanti ◽  
...  
Keyword(s):  
Prostate Carcinoma ◽  
Myeloid Cell ◽  
Human Prostate ◽  
Cell Recruitment ◽  
Human Prostate Carcinoma ◽  
Carcinoma Associated Fibroblasts

scholarly journals ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

2019 ◽  
Vol 116 (14) ◽  
pp. 6836-6841 ◽  
Author(s):  
Vinit Shanbhag ◽  
Kimberly Jasmer-McDonald ◽  
Sha Zhu ◽  
Adam L. Martin ◽  
Nikita Gudekar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lysyl Oxidase ◽  
Meta Analysis ◽  
Myeloid Cell ◽  
Breast Cancer Patients ◽  
Orthotopic Mouse Model ◽  
Copper Transporter ◽  
Cell Recruitment ◽  
Lung Carcinoma Cells ◽  
Lewis Lung Carcinoma Cells

Lysyl oxidase (LOX) and LOX-like (LOXL) proteins are copper-dependent metalloenzymes with well-documented roles in tumor metastasis and fibrotic diseases. The mechanism by which copper is delivered to these enzymes is poorly understood. In this study, we demonstrate that the copper transporter ATP7A is necessary for the activity of LOX and LOXL enzymes. Silencing of ATP7A inhibited LOX activity in the 4T1 mammary carcinoma cell line, resulting in a loss of LOX-dependent mechanisms of metastasis, including the phosphorylation of focal adhesion kinase and myeloid cell recruitment to the lungs, in an orthotopic mouse model of breast cancer. ATP7A silencing was also found to attenuate LOX activity and metastasis of Lewis lung carcinoma cells in mice. Meta-analysis of breast cancer patients found that high ATP7A expression was significantly correlated with reduced survival. Taken together, these results identify ATP7A as a therapeutic target for blocking LOX- and LOXL-dependent malignancies.

scholarly journals Diverse myeloid cells are recruited to the developing and inflamed mammary gland

2020 ◽  
Author(s):  
Gillian J Wilson ◽  
Ayumi Fukuoka ◽  
Francesca Vidler ◽  
Gerard J Graham
Keyword(s):  
Mammary Gland ◽  
Pubertal Timing ◽  
Myeloid Cell ◽  
Mammary Glands ◽  
Sterile Inflammation ◽  
Cell Compartment ◽  
Cell Recruitment ◽  
Terminal End Buds ◽  
Functional Consequences ◽  
Inflammatory Burden

AbstractThe immune system plays fundamental roles in the mammary gland, shaping developmental processes and controlling inflammation during infection and cancer. Here we reveal unanticipated heterogeneity in the myeloid cell compartment during development of virgin, pregnant and involuting mouse mammary glands, and in milk. We investigate the functional consequences of individual and compound chemokine receptor deficiency on cell recruitment. Diverse myeloid cell recruitment was also shown in models of sterile inflammation and bacterial infection. Strikingly, we have shown that inflammation and infection can alter the abundance of terminal end buds, a key developmental structure, within the pubertal mammary gland. This previously unknown effect of inflammatory burden during puberty could have important implications for understanding the control of pubertal timing.

scholarly journals Myeloid cell recruitment versus local proliferation differentiates susceptibility from resistance to filarial infection

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sharon M Campbell ◽  
Johanna A Knipper ◽  
Dominik Ruckerl ◽  
Conor M Finlay ◽  
Nicola Logan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inbred Mouse ◽  
Myeloid Cell ◽  
Mouse Strains ◽  
Dependent Manner ◽  
Filarial Infection ◽  
Cell Recruitment ◽  
Litomosoides Sigmodontis ◽  
Age Dependent ◽  
Effector Response

Both TH2-dependent helminth killing and suppression of the TH2 effector response have been attributed to macrophages (MΦ) activated by IL-4 (M(IL-4)). To investigate how M(IL-4) contribute to diverse infection outcomes, the MΦ compartment of susceptible BALB/c mice and more resistant C57BL/6 mice was profiled during infection of the pleural cavity with the filarial nematode, Litomosoides sigmodontis. C57BL/6 mice exhibited a profoundly expanded resident MΦ (resMΦ) population, which was gradually replenished from the bone marrow in an age-dependent manner. Infection status did not alter the bone-marrow derived contribution to the resMΦ population, confirming local proliferation as the driver of resMΦ expansion. Significantly less resMΦ expansion was observed in the susceptible BALB/c strain, which instead exhibited an influx of monocytes that assumed an immunosuppressive PD-L2+ phenotype. Inhibition of monocyte recruitment enhanced nematode killing. Thus, the balance of monocytic vs. resident M(IL-4) numbers varies between inbred mouse strains and impacts infection outcome.

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