scholarly journals The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1584
Author(s):  
Vasileia Ismini Alexaki

Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in it. The present review discusses the effects of obesity, chronic peripheral inflammation and obesity-associated metabolic and endocrine perturbations, including insulin resistance, dyslipidemia and increased glucocorticoid levels, on microglial function.

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi127-vi127
Author(s):  
Adam Grippin ◽  
Brandon Wummer ◽  
Hector Mendez-Gomez ◽  
Brian Stover ◽  
Jianping Huang ◽  
...  

Abstract BACKGROUND While dendritic cell (DC) vaccine therapy has shown considerable promise for glioblastoma (GBM) patients (Mitchell et al. Nature, 2015), their advancement into human clinical trials has been fraught with challenges in the development, manufacturing, and marketing of successful cancer immunotherapies. To circumvent the challenges associated with cell therapy, we have developed a new platform technology consisting of tumor derived mRNA complexed into lipid-nanoparticles (RNA-NPs) for systemic delivery to DCs in vivo and induction of antigen specific T cell immunity against GBM. OBJECTIVES/ METHODS We sought to assess if surface and charge modifications to our custom lipid-NP could facilitate its localization to lymphoid organs and the brain tumor microenvironment. RESULTS We demonstrate that intravenous administration of our unmodified custom RNA-NPs mediate systemic activation of DCs; these include activation of CD11c+ cells in the brains of animals with intact blood brain-barriers (BBBs). RNA-NPs mediate antigen specific T cell immunity and anti-tumor efficacy with increased tumor infiltrating lymphocytes against a NF-1/p53 mutant glioma that recapitulates features of human GBM in immunocompetent mice. Modification of surface charge could direct these RNA-NPs to lymphoid organs (e.g. spleen, lymph nodes) while modification of the lipid backbone (with cholesterol) enhances localization to innate immune cells in NF-1/p53 mutant and GL261 gliomas. We therefore assessed if this customizable lipid-NP could be leveraged for delivery of immune checkpoint inhibitors (ICIs) (i.e. PD-L1 siRNA) to the brain tumor microenvironment. Compared with scrambled siRNA-NPs in combination with ICIs, surface modified siRNA-NPs (antagonizing PD-L1) in combination with ICIs mediated significant antitumor efficacy with 37% long term survivors in an otherwise fatal brain tumor model. CONCLUSION We designed multifunctional RNA-NPs with a simple, scalable synthesis method that enables delivery of nucleic acids to innate immune cells in lymphoid organs and brain tumors.


2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Valbona Mirakaj

Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201839) and Li et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210008) describe the impact of the innate immune system on the development of cardiovascular disease.


Sexual Health ◽  
2011 ◽  
Vol 8 (4) ◽  
pp. 453 ◽  
Author(s):  
Anna C. Hearps ◽  
Thomas A. Angelovich ◽  
Anthony Jaworowski ◽  
John Mills ◽  
Alan L. Landay ◽  
...  

The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.


2010 ◽  
Vol 7 (1) ◽  
pp. 62 ◽  
Author(s):  
Kristian P Doyle ◽  
Egle Cekanaviciute ◽  
Lauren E Mamer ◽  
Marion S Buckwalter

2020 ◽  
Vol 21 (24) ◽  
pp. 9695
Author(s):  
Benjamin J. Swartzwelter ◽  
Alexandra C. Fux ◽  
Litty Johnson ◽  
Elmer Swart ◽  
Sabine Hofer ◽  
...  

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate matter, i.e., engineered nanoparticles. Nanoparticles are not inherently pathogenic, and yet cases have been described in which specific nanoparticle types can either induce innate/inflammatory responses or modulate the activity of activated innate cells. Many of these studies rely upon activation by agonists of toll-like receptors, such as lipopolysaccharide or peptidoglycan, instead of the more realistic stimulation by whole live organisms. In this review we examine and discuss the effects of nanoparticles on innate immune cells activated by live bacteria. We focus in particular on how nanoparticles may interfere with bacterial processes in the context of innate activation, and confine our scope to the effects due to particles themselves, rather than to molecules adsorbed on the particle surface. Finally, we examine the long-lasting consequences of coexposure to nanoparticles and bacteria, in terms of potential microbiome alterations and innate immune memory, and address nanoparticle-based vaccine strategies against bacterial infection.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yogesh Saxena ◽  
Sanjeev Routh ◽  
Arunika Mukhopadhaya

Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as ‘bone remodeling’. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term “immunoporosis” to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.


2018 ◽  
Vol 215 (9) ◽  
pp. 2235-2245 ◽  
Author(s):  
Silvia S. Kang ◽  
Mark T.W. Ebbert ◽  
Kelsey E. Baker ◽  
Casey Cook ◽  
Xuewei Wang ◽  
...  

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. Using this approach in models of amyloidosis, tauopathy, and aging, we revealed a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, aged females demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.


2018 ◽  
Vol 115 (7) ◽  
pp. E1608-E1617 ◽  
Author(s):  
Christian Madry ◽  
I. Lorena Arancibia-Cárcamo ◽  
Vasiliki Kyrargyri ◽  
Victor T. T. Chan ◽  
Nicola B. Hamilton ◽  
...  

Microglia, the brain’s innate immune cells, have highly motile processes which constantly survey the brain to detect infection, remove dying cells, and prune synapses during brain development. ATP released by tissue damage is known to attract microglial processes, but it is controversial whether an ambient level of ATP is needed to promote constant microglial surveillance in the normal brain. Applying the ATPase apyrase, an enzyme which hydrolyzes ATP and ADP, reduces microglial process ramification and surveillance, suggesting that ambient ATP/ADP maintains microglial surveillance. However, attempting to raise the level of ATP/ADP by blocking the endogenous ecto-ATPase (termed NTPDase1/CD39), which also hydrolyzes ATP/ADP, does not affect the cells’ ramification or surveillance, nor their membrane currents, which respond to even small rises of extracellular [ATP] or [ADP] with the activation of K+ channels. This indicates a lack of detectable ambient ATP/ADP and ecto-ATPase activity, contradicting the results with apyrase. We resolve this contradiction by demonstrating that contamination of commercially available apyrase by a high K+ concentration reduces ramification and surveillance by depolarizing microglia. Exposure to the same K+ concentration (without apyrase added) reduced ramification and surveillance as with apyrase. Dialysis of apyrase to remove K+ retained its ATP-hydrolyzing activity but abolished the microglial depolarization and decrease of ramification produced by the undialyzed enzyme. Thus, applying apyrase affects microglia by an action independent of ATP, and no ambient purinergic signaling is required to maintain microglial ramification and surveillance. These results also have implications for hundreds of prior studies that employed apyrase to hydrolyze ATP/ADP.


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