scholarly journals Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1323
Author(s):  
Gabriela Rapozo Guimarães ◽  
Palloma Porto Almeida ◽  
Leandro de Oliveira Santos ◽  
Leane Perim Rodrigues ◽  
Juliana Lott de Carvalho ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Cellular Proliferation ◽  
Immune Cell ◽  
Disease Onset ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Cell Type ◽  
Innate And Adaptive Immunity ◽  
Age Related ◽  
Effects Of Aging

The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.

Effects of Aging and TGF-Beta 3 on Chondrocyte and Mesenchymal Stem Cell Matrix Formation

2010 ◽  
Author(s):  
Isaac E. Erickson ◽  
Steven C. van Veen ◽  
Swarnali Sengupta ◽  
Sydney R. Kestle ◽  
Jason A. Burdick ◽  
...  
Keyword(s):  
Stem Cells ◽  
Articular Chondrocytes ◽  
Cell Types ◽  
Matrix Proteins ◽  
Cell Type ◽  
Cell Matrix ◽  
Age Related ◽  
Cartilage Restoration ◽  
Effects Of Aging

Articular cartilage pathology is common in the aged population. Numerous studies have shown that aged chondrocytes (CHs) are inferior to juvenile CHs in their ability to proliferate and produce cartilage-specific extracellular matrix proteins, potentially limiting their use in tissue engineering applications for cartilage restoration [1,2]. Mesenchymal stem cells (MSCs) are an alternative cell type that can be expanded in vitro while maintaining their ability to differentiate into cell types comparable to articular chondrocytes. However, organismal aging also influences human MSC proliferation [3,4] and multi-potential differentiation [5], though for chondrogenesis these findings are mixed, with some suggesting that aged progenitor cells retain their chondrogenic capacity [6]. The objective of this study was to assess age related differences in donor-matched CH and MSC potential for chondrogenic repair. In addition, the effects of the chondrogenic growth factor TGF-β3 on CHs and MSCs were evaluated.

The Intersection of Metformin and Inflammation

2021 ◽  
Author(s):  
Leena P. Bharath ◽  
Barbara S. Nikolajczyk
Keyword(s):  
Mitochondrial Function ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Remarkable Effect ◽  
Tumor Onset ◽  
Age Related ◽  
Immune Mediated ◽  
Autoimmune Conditions ◽  
Near Term

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy, is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. Here we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

scholarly journals Type 2 Innate Immunity in Helminth Infection Is Induced Redundantly and Acts Autonomously following CD11c+Cell Depletion

2012 ◽  
Vol 80 (10) ◽  
pp. 3481-3489 ◽  
Author(s):  
Katherine A. Smith ◽  
Yvonne Harcus ◽  
Natalio Garbi ◽  
Günter J Hämmerling ◽  
Andrew S. MacDonald ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Immune Cell ◽  
Cell Types ◽  
Alternative Activation ◽  
Gastrointestinal Helminths ◽  
Antibody Treatment ◽  
Dominant Type ◽  
Content Type ◽  
Arginase 1

ABSTRACTInfection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11chighdendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, includingHeligmosomoides polygyrusandNippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11chighcells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11chighcells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-α, and Ym-1 (Chi3L3) in the intestine followingH. polygyrusinfection or in the lung followingN. brasiliensisinfection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-β in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid (“nuocyte”) populations all proceeded irrespective of depletion of CD11chighcells or basophils. Thus, while CD11chighDCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection.

scholarly journals Jointly leveraging spatial transcriptomics and deep learning models for pathology image annotation improves cell type identification over either approach alone.

2021 ◽  
Author(s):  
Asif Zubair ◽  
Richard H. Chapple ◽  
Sivaraman Natarajan ◽  
William C. Wright ◽  
Min Pan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Image Annotation ◽  
Cell Types ◽  
Tissue Cell ◽  
Cell Type ◽  
Spatially Resolved ◽  
Transcriptomics Data ◽  
Diagnostic Applications ◽  
The Many ◽  
Level Performance

The disorganization of cell types within tissues underlies many human diseases and has been studied for over a century using the conventional tools of pathology, including tissue-marking dyes such as the H&E stain. Recently, spatial transcriptomics technologies were developed that can measure spatially resolved gene expression directly in pathology-stained tissues sections, revealing cell types and their dysfunction in unprecedented detail. In parallel, artificial intelligence (AI) has approached pathologist-level performance in computationally annotating H&E images of tissue sections. However, spatial transcriptomics technologies are limited in their ability to separate transcriptionally similar cell types and AI-based pathology has performed less impressively outside their training datasets. Here, we describe a methodology that can computationally integrate AI-annotated pathology images with spatial transcriptomics data to markedly improve inferences of tissue cell type composition made over either class of data alone. We show that this methodology can identify regions of clinically relevant tumor immune cell infiltration, which is predictive of response to immunotherapy and was missed by an initial pathologist's manual annotation. Thus, combining spatial transcriptomics and AI-based image annotation has the potential to exceed pathologist-level performance in clinical diagnostic applications and to improve the many applications of spatial transcriptomics that rely on accurate cell type annotations.

scholarly journals MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

2019 ◽  
Author(s):  
Elmer A. Fernández ◽  
Yamil D. Mahmoud ◽  
Florencia Veigas ◽  
Darío Rocha ◽  
Mónica Balzarini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Therapy Response ◽  
Cell Types ◽  
Gene Signature ◽  
Response To Therapy ◽  
Support Vector ◽  
Data Sets ◽  
Cell Type ◽  
Before And After

AbstractRNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to over-estimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Julien Racle ◽  
Kaat de Jonge ◽  
Petra Baumgaertner ◽  
Daniel E Speiser ◽  
David Gfeller
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Types ◽  
Response To Therapy ◽  
Expression Data ◽  
Cell Type ◽  
Tumor Gene Expression ◽  
Tumor Gene

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type-specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org).

scholarly journals Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Nathaniel S. Woodling ◽  
Arjunan Rajasingam ◽  
Lucy J. Minkley ◽  
Alberto Rizzo ◽  
Linda Partridge
Keyword(s):  
Glial Cell ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Developmental Timing ◽  
Cell Type ◽  
Specific Effects ◽  
Trade Offs ◽  
Distinct Cell ◽  
Pi3k Signalling ◽  
Cell Type Specific

Abstract Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

scholarly journals Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

2020 ◽  
Vol 21 (19) ◽  
pp. 7165 ◽  
Author(s):  
Denisa Baci ◽  
Annalisa Bosi ◽  
Luca Parisi ◽  
Giuseppe Buono ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Cells ◽  
Cardiac Fibrosis ◽  
Immune Cell ◽  
Tissue Injury ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Sterile Inflammation ◽  
Therapeutic Interventions ◽  
Ecm Remodeling

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in “sterile” inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.

scholarly journals Fibroblasts – the neglected cell type in peripheral sensitization and chronic pain? - A systematic view on the current state of the literature

2021 ◽  
Author(s):  
Naomi Shinotsuka ◽  
Franziska Denk
Keyword(s):  
Chronic Pain ◽  
Cell Function ◽  
Immune Cell ◽  
Data Extraction ◽  
Cell Types ◽  
Extraction Methods ◽  
Peripheral Sensitization ◽  
Cell Type ◽  
Systematic Screening ◽  
Pain Research

AbstractChronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. We now know that besides an obvious role for neuronal populations in the peripheral and central nervous system, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell-type that appears to be rather neglected in this context: the humble fibroblast.Fibroblasts may seem unassuming, but actually play a major part in regulating immune cell function and driving chronic inflammation. What is known about them in the context chronic pain?Here we set out to analyze the literature on this topic – using systematic screening and data extraction methods to obtain a balanced view on what has been published. We found that there has been surprisingly little research in this area: 134 articles met our inclusion criteria, only a tiny minority of which directly investigated interactions between fibroblasts and peripheral neurons. We categorized the articles we included – stratifying them according to what was investigated, the estimated quality of results, and any common conclusions.Fibroblasts are a ubiquitous cell type and a prominent source of many pro-algesic mediators in a wide variety of tissues. We think that they deserve a more central role in pain research and propose a new, testable model of how fibroblasts might drive peripheral neuron sensitization.

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