A new study published in Cell Host and Microbe by Dr. Dawn Bowdish’s group, demonstrates the effect of the aging on the microbiota and how these changes drive intestinal permeability, age-associated inflammation, and decreased macrophage function. The study, co-authored by Netusha Thevaranjan and Alicja Puchta, uses multiple mouse models to show that age-associated inflammation is driven by an aging microbiota, and reducing TNF levels can reverse both age-related microbial changes and inflammation. This has important implications regarding how maintaining a healthy microbiome and reversing age-related microbial changes can help improve our health as we grow older. Read the full story here.

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In the article entitled Innate Immune Cytokines, Fibroblast Phenotypes, and Regulation of Extracellular Matrix in Lung,” Carl Richards, PhDMcMaster University, Hamilton, Canada, examines the scientific evidence suggesting that cytokines stimulated by the innate immune system can directly control fibroblast behavior. Fibroblasts are major contributors to extracellular remodeling and regulate the accumulation of inflammatory cells, which can lead to chronic inflammation and ultimately to organ dysfunction. Dr. Richards discusses the potential of metabolic changes, age, and epigenetic mechanisms to affect the activity of fibroblasts and immune system cell populations through impact on cytokine-mediated signaling pathways.

“Dr. Richards has made major contributions to our understanding of cytokine mediated effects on inflammatory disorders mediated through interactions between the immune system and resident fibroblasts,” says Journal of Interferon & Cytokine Research Co-Editor-in-Chief Thomas Hamilton, Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH. “This review provides a highly relevant discussion of these issues and is particularly timely as our ability to use this knowledge is enabling new therapeutic strategies to treat inflammation-related chronic disease.”

The annual Medical Sciences Research Day took place on January 25th and several MIRC trainees were selected to feature their work at this day-long research event. From oral talks, to poster presentations, students did a great job representing MIRC and their respective research groups. Lisa Newhook (Bramson), Joanne Hammill (Bramson), Sara Dizzell (Kaushic) and Puja Bagri (Kaushic) all gave excellent oral presentations, while Donald Basin (Wan), Jessica Breznik (Bowdish), Grace Teskey (Bowdish), Anisha Dubey (Richards) and Danielle Vitali (Kaushic) did an exceptional job with their poster presentations. Congratulations to all presenters for a job well done! Just a reminder, all MIRC graduate students are welcome to submit abstracts for the upcoming Health Sciences Research Plenary, which will be taking place in May. 

 

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Congratulations to Amanda Lee, a PhD candidate in Dr. Ali Ashkar's lab, on her recent publication in the Journal of Experimental Medicine. The elaborate study thoroughly describes the mechanism by which NK cells are activated during mucosal viral infection. Using ain vivo mouse model of vaginal HSV-2 infection, Lee et al. showed that type I IFNs signal through inflammatory monocytes to produce IL-18, which then activates NK cells to produce IFN-gamma and augments protection against HSV-2 infection. The study was featured on the IIDR website,and the full study can be found here.

Thanks everyone for supporting The Good Samaritan Children's Home in Nairobi, Kenya at yesterday's Bake Sale!

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Endotoxin, or LPS tolerance, is an immunomodulatory mechanism that protects the host against secondary LPS exposure and may prevent endotoxic shock. During the development of tolerance, LPS binds to TLR4 and signals the release of cytokines including type I IFN, which has shown to have immunomodulator properties. The role of type I IFN in the induction of LPS tolerance was the topic of interest in a recent publication by Dr. Ali Ashkar’s research group. The study, led by former undergraduate thesis student Yalda Karimi, suggests that type I IFN does not play a role in LPS tolerance in vitro. Examining peritoneal macrophages from both wild type and IFNR KO mice in vitro, they showed that there is comparable, reduced cytokine production after secondary LPS exposure. In addition, both strains of mice received small doses of LPS to induce tolerance, and were then protected from a lethal dose of LPS. The results from this study show that unlike what was expected, type I IFN does not seem to play a role in endotoxin tolerance, and further studies are required to understand the exact mechanisms leading to tolerance. Read the full study here.

 

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Individuals who are allergic to foods such as nuts and shellfish, suffer from these allergies for the entirety of their lives, with no disease-transforming therapies currently available. Better understanding food allergy is an important area of research in Dr. Manal Jordana’s lab and a recent study led by post-doctoral fellow Dr. Rodrigo Jiménez-Saiz that was published in the Journal of Allergy and Clinical Immunology, looks at the underlying mechanisms involved in allergic responses to food allergens. The conventional belief is that lifelong IgE in food allergy is due to the generation of IgE-producing plasmablasts by germinal center B cells.

These IgE-producing plasmablasts travel to the bone marrow, where they secrete IgE for the rest of an allergic individual’s life. However, this study shows a novel mechanism to explain persistent IgE in allergic responses. Using various animal models and in vitro assays, Jiménez-Saiz et al. showed that lifelong food allergy is the result of the activation of allergen-specific long-lived memory B-cells, which upon allergen re-exposure, replenish allergen-specific IgE-secreting plasma cells in an IL-4-producing CD4 T cell dependent manner. This is a novel finding, and is especially impressive due to the extremely rare population of antigen-specific IgE+ memory cells that Drs. Jiménez-Saiz and Chu were able to study in the animals across a prolonged period of time.

Furthermore, this work suggests that lifelong food allergies may be the result of re-exposure to allergens which recurrently activate memory B and CD4 T cells, and that the mechanisms involved in activating and maintaining these memory responses should be targeted in the search of potential therapies for IgE-mediated food allergies.  The paper is now available to read online here. Congratulations to Rodrigo, and the entire Jordana lab for this great work and achievement! 

Although NK cells are known to play a critical role in protecting against the development of cancer, NK cells become dysfunction due to the tumor microenvironment. The mechanisms by which the local tumor environment inhibits NK cell function are not well described. A study by Dr. Ali Ashkar’s group examining the interactions between the tumor microenvironment and murine NK cells recently reported that both M2-polarized macrophages and tumor-associated macrophages (TAMs) inhibit NK cell expression and cytotoxicity in a contact-dependent manner. Furthermore, they showed that the suppressive effective of these macrophages was due to TGF-β. This study presents a novel method to describe macrophage-mediated regulation of NK cells in a tumor.  

MIRC is an excellent research facility largely thanks to extremely talented trainees who work tirelessly to help progress research in their respective fields of work. As such, we would like to highlight these hardworking individuals on our website and share their stories with all of you. If you are interested in participating in this series or would like to nominate a peer, please contact Puja Bagri (This email address is being protected from spambots. You need JavaScript enabled to view it.). We look forward to featuring the excellence of our talented trainees very soon! 

Humanized mouse models, where human tissues are housed in the background of a mouse, allow researchers to directly examine human cells in a biological system. Development of this model has enabled the study of human-specific pathogens, and has considerably expanded the ability to conduct mechanistic, basic science research. MIRC members are fortunate to have access to humanized mice, thanks to the work being done in Dr. Ali Ashkar’s lab. A recent paper from Dr. Ali Ashkar’s research group provides greater detail about their highly regarded humanized mouse model. They compared two different methods of human stem cell engraftment, were mice were engrafted with human cord blood intravenously as adults or intrahepatically as newborns. They found that mice engrafted as newborns initially had higher levels of human CD3+ T cells and lower levels of human B cells in the blood. However, levels of human CD45 cells were comparable long-term in both adult and newborn mice, suggesting there is very little difference in human immune cell reconstitution between the two methods. When looking at reconstitution in different immunological tissues, they found significant levels of human immune cell reconstitution in all sites, including mesenteric lymph nodes and the liver. This is an interesting finding, as not much has been shown about the reconstitution of lymph nodes and the liver. Furthermore, this study suggests that this humanized mouse model can be used as a relevant pre-clinical model to study the human immune system in the gastrointestinal tract.

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