Mendiola Lab

Decoding the neuroimmune and blood crosstalk in neurological diseases

Transcriptional mechanisms of neurotoxic microglia in neurological diseases

Neurovascular mechanisms of oxidative stress and mitochondrial dysfunction

Oxidative stress and chromatin architecture in innate immunity

Research Vision

Unchecked brain inflammation contributes to neurological disease progression, however how the brain’s immune system becomes harmful to neurons is largely unknown. Our neuroimmunology research investigates the role that brain innate immune responses play in the initiation and progression of neurological diseases. We integrate systems neuroimmunology and functional genomics with disease models to study how the brain-immune-blood axis regulates epigenetic circuits, oxidative stress, and mitochondrial control of neuroinflammation in multiple sclerosis and Alzheimer’s disease. The aim is to understand and manipulate the brain’s immune system with the goal of engineering new methods to protect the brain from harmful inflammation and neurodegeneration.

Recent Work

Andrew S. Mendiola, Zhaoqi Yan, Karuna Dixit, Jeffrey R. Johnson, Mehdi Bouhaddou, Anke Meyer-Franke, Min-Gyoung Shin, Yu Yong, Ayushi Agrawal, Eilidh MacDonald, Gayathri Muthukumar, Clairice Pearce, Nikhita Arun, Belinda Cabriga, Rosa Meza-Acevedo, Maria del Pilar S. Alzamora, Scott S. Zamvil, Alexander R. Pico, Jae Kyu Ryu, Nevan J. Krogan & Katerina Akassoglou

Nature Immunology | July 2023 Vol. 24 No.7

Defining blood-induced microglia functions in neurodegeneration through multiomic profiling

Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer’s disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

Andrew S. Mendiola, Jae Kyu Ryu, Sophia Bardehle, Anke Meyer-Franke, Kenny Kean-Hooi Ang, Chris Wilson, Kim M. Baeten, Kristina Hanspers, Mario Merlini, Sean Thomas, Mark A. Petersen, Alexander Williams, Reuben Thomas, Victoria A. Rafalski, Rosa Meza-Acevedo, Reshmi Tognatta, Zhaoqi Yan, Samuel J. Pfaff, Michael R. Machado, Catherine Bedard, Pamela E. Rios Coronado, Xiqian Jiang, Jin Wang, Michael A. Pleiss, Ari J. Green, Scott S. Zamvil, Alexander R. Pico, Benoit G. Bruneau, Michelle R. Arkin & Katerina Akassoglou

Nature Immunology | May 2020 Vol. 21 No.7

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress–producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.

Join Our Team

The Mendiola Laboratory is grounded in the principle of inclusive excellence in science, ensuring that everyone, especially those from marginalized groups, feels valued and empowered to achieve career prosperity. We are committed to diversity, equity, and inclusion to enable a path for everyone to thrive in.

Our research program aims to impact our fundamental knowledge of microglia physiology and how the brains immune system deviates in function during disease. We are looking for bold, creative, and rigorous scientists to join our team. Contact Dr. Mendiola if you share a passion for bridging multiple disciplines and applying cutting-edge technologies to tackle research questions in multiple sclerosis and Alzheimer’s disease.