Periodic Reporting for period 1 - CD300f (Unravelling the role of the immune receptor CD300f in spinal cord injury and metabolic reprogramming)
Reporting period: 2021-10-01 to 2023-09-30
Spinal cord injury (SCI) is a leading cause of death and disability in individuals under 40, mainly men. The societal and individual costs of SCI are significant, yet there is currently no effective treatment for humans. SCI induces systemic immune suppression and triggers a local inflammatory response in the injured spinal cord, leading to secondary damage. While inflammation is crucial for homeostasis, the balance between destructive and protective aspects must be precisely regulated for CNS repair and recovery. Recent focus has been on immune receptors as potential targets for controlling microglia/macrophage responses post-SCI.
The project aims to assess the role of the CD300f immune receptor and its metabolic reprogramming in neurorestoration after SCI. Additionally, the efficiency of a mitochondrial modulator as a novel neuroprotective strategy is being tested. The study involved inducing spinal cord contusion injury in CD300f knockout mice, evaluating functional outcomes and histopathological parameters.
The project aims to assess the role of the CD300f immune receptor and its metabolic reprogramming in neurorestoration after SCI. Additionally, the efficiency of a mitochondrial modulator as a novel neuroprotective strategy is being tested. The study involved inducing spinal cord contusion injury in CD300f knockout mice, evaluating functional outcomes and histopathological parameters.
The study observed worsened functional outcomes in CD300f KO mice after spinal cord injury (SCI), confirmed through additional experiments (Fig1A). While myelin sparing at 28 days post-injury (dpi) did not differ (Fig1B), staining for Oil Red O indicated increased lipid accumulation in CD300f KO mice, suggesting altered phagocytosis and/or impaired lipid degradation (Fig1C).
To delve into CD300f's role in myelin phagocytosis and lipid degradation, Bone Marrow-Derived Macrophages (BMDMs) from WT and CD300f KO mice were evaluated. While myelin phagocytosis showed no differences (Fig2A-B), BMDMs from CD300f KO female mice exhibited greater neutral lipid accumulation (Fig2C). This suggests CD300f deficiency may impact myelin degradation and lipid droplet biosynthesis, crucial for resolving inflammation and promoting healing after SCI.
Demyelination generates toxic lipids like oxidized phosphatidylcholine (OxPC). CD300f's potential to bind and detoxify OxPC was explored, showing increased axonal pathology in CD300f KO mice injected with OxPC, suggesting a role in detoxifying toxic lipids (Fig3). Mechanisms behind CD300f's detoxification need further study.
The proposal aimed to assess the neuroprotective potential of DCA, an immunometabolic modulator, in SCI. DCA treatment in WT and CD300f-KO mice with spinal cord contusion injury showed slight improvement, but no statistical differences (Figure not provided). Given CD300f-KO mice's impaired lipid processing, the study explored Liver X receptor (LXR) agonist (GW3965) treatment, finding no statistical differences in functional outcomes. Further exploration, particularly using BMDMs experiments, is planned before in vivo experiments continue.
The scientific community was mainly reached through scientific publications in high profile journals and communications to precisely selected international meetings. As mentioned above, during this period, we published two manuscripts in peer-reviewed journals, one of them as a corresponding author. We disseminated our results also in international and national meetings. My PhD student Bruno Pannunzio presented their results in the Sfn Neuroscience meeting in November 2021 and in a national meeting in Uruguay in the same year. Moreover, I presented myself his results in the European Glia meeting in Berlin (July 2023) and Andres Cawen (my former master thesis’ student) presented his results about the involvement of CD300f in spinal cord injury, in the same meeting. Some results obtained during this period of time and thanks to the fellowship were part of the Cell Reports publication and were disseminated by Dr Hugo Peluffo in the Keystone lectures in Colorado (USA) in 2023.
Throughout the project, every effort was made to disseminate the existence of the project, its progress and the scientific results obtained to as wide audience as possible. For this aim, we used the website at different levels. The group own a website (https://npir.uab.cat(opens in new window)) that is used to give visibility to our project and our research, but also dissemination in open days of the Institute of Neurosciences (UAB) or at high school level.
To delve into CD300f's role in myelin phagocytosis and lipid degradation, Bone Marrow-Derived Macrophages (BMDMs) from WT and CD300f KO mice were evaluated. While myelin phagocytosis showed no differences (Fig2A-B), BMDMs from CD300f KO female mice exhibited greater neutral lipid accumulation (Fig2C). This suggests CD300f deficiency may impact myelin degradation and lipid droplet biosynthesis, crucial for resolving inflammation and promoting healing after SCI.
Demyelination generates toxic lipids like oxidized phosphatidylcholine (OxPC). CD300f's potential to bind and detoxify OxPC was explored, showing increased axonal pathology in CD300f KO mice injected with OxPC, suggesting a role in detoxifying toxic lipids (Fig3). Mechanisms behind CD300f's detoxification need further study.
The proposal aimed to assess the neuroprotective potential of DCA, an immunometabolic modulator, in SCI. DCA treatment in WT and CD300f-KO mice with spinal cord contusion injury showed slight improvement, but no statistical differences (Figure not provided). Given CD300f-KO mice's impaired lipid processing, the study explored Liver X receptor (LXR) agonist (GW3965) treatment, finding no statistical differences in functional outcomes. Further exploration, particularly using BMDMs experiments, is planned before in vivo experiments continue.
The scientific community was mainly reached through scientific publications in high profile journals and communications to precisely selected international meetings. As mentioned above, during this period, we published two manuscripts in peer-reviewed journals, one of them as a corresponding author. We disseminated our results also in international and national meetings. My PhD student Bruno Pannunzio presented their results in the Sfn Neuroscience meeting in November 2021 and in a national meeting in Uruguay in the same year. Moreover, I presented myself his results in the European Glia meeting in Berlin (July 2023) and Andres Cawen (my former master thesis’ student) presented his results about the involvement of CD300f in spinal cord injury, in the same meeting. Some results obtained during this period of time and thanks to the fellowship were part of the Cell Reports publication and were disseminated by Dr Hugo Peluffo in the Keystone lectures in Colorado (USA) in 2023.
Throughout the project, every effort was made to disseminate the existence of the project, its progress and the scientific results obtained to as wide audience as possible. For this aim, we used the website at different levels. The group own a website (https://npir.uab.cat(opens in new window)) that is used to give visibility to our project and our research, but also dissemination in open days of the Institute of Neurosciences (UAB) or at high school level.
The study's potential impact on acute spinal cord injury (SCI) treatment in humans is significant, offering a promising strategy to reduce secondary damage and functional loss. Currently lacking effective clinical treatments for SCI, this research could pave the way for innovative approaches. Additionally, the project contributes to advancing knowledge on the endogenous regulation of the neuroinflammatory response, crucial for developing therapeutic strategies. These insights not only hold promise for preventing neuronal damage progression but also offer opportunities for tissue regeneration. Beyond SCI, identifying common neuroinflammatory pathways may extend these benefits to neurodegenerative diseases like Alzheimer's and autoimmune diseases such as Multiple Sclerosis.
SCI is a major cause of death and disability in those under 40, peaking around 20 years. In the European Union, there were approximately 330,000 SCI patients in 2002, with around 13,000 new cases annually. The male-to-female ratio is about 4:1, and the mean age at injury varies across countries. The societal and individual costs of SCI-induced paralysis are substantial, with estimated lifetime costs per individual reaching $1 million in the USA. Annually, 4 billion euros are spent on SCI patient management and care, with potential higher costs in the expanded European Community. These figures exclude social costs and the challenges faced by affected individuals and their families. Adaptations like changing living quarters, vehicle modifications, and addressing everyday difficulties affect both the individual's life and society economically.
SCI has profound social consequences, impacting employment rates, with only 24% of quadriplegic and 34% of paraplegic patients employed eight years post-injury. Despite these challenges and the considerable socioeconomic burden, effective SCI treatment remains elusive. Recognizing the need for new recovery-promoting strategies, the European Assembly emphasizes the importance of intensified efforts in spinal cord injury research, highlighting prevention and financial support. In light of these factors, the study not only addresses a critical gap in SCI treatment but aligns with the broader call for comprehensive policies and advancements in disability research.
During this period, I had two publications in peer-review journals, one addressing the involvement of another immune receptor, CD200R1, in peripheral nerve regeneration, and the other addressing the role of CD300f in inflammaging (see publications). We are currently preparing a manuscript with the results obtained from this proposal and they will be part of the data necessary for applying to International Research Paraplegia (IRP) funding and for applying for funding calls from the Spanish government. Moreover, during this period I directed two master theses involving the role of CD300f in demyelination and a PhD thesis in the role of CD200R1. Finally, this fellowship allowed me a successful reintegration as I currently hold a Tenure lecture position at the host institution.
SCI is a major cause of death and disability in those under 40, peaking around 20 years. In the European Union, there were approximately 330,000 SCI patients in 2002, with around 13,000 new cases annually. The male-to-female ratio is about 4:1, and the mean age at injury varies across countries. The societal and individual costs of SCI-induced paralysis are substantial, with estimated lifetime costs per individual reaching $1 million in the USA. Annually, 4 billion euros are spent on SCI patient management and care, with potential higher costs in the expanded European Community. These figures exclude social costs and the challenges faced by affected individuals and their families. Adaptations like changing living quarters, vehicle modifications, and addressing everyday difficulties affect both the individual's life and society economically.
SCI has profound social consequences, impacting employment rates, with only 24% of quadriplegic and 34% of paraplegic patients employed eight years post-injury. Despite these challenges and the considerable socioeconomic burden, effective SCI treatment remains elusive. Recognizing the need for new recovery-promoting strategies, the European Assembly emphasizes the importance of intensified efforts in spinal cord injury research, highlighting prevention and financial support. In light of these factors, the study not only addresses a critical gap in SCI treatment but aligns with the broader call for comprehensive policies and advancements in disability research.
During this period, I had two publications in peer-review journals, one addressing the involvement of another immune receptor, CD200R1, in peripheral nerve regeneration, and the other addressing the role of CD300f in inflammaging (see publications). We are currently preparing a manuscript with the results obtained from this proposal and they will be part of the data necessary for applying to International Research Paraplegia (IRP) funding and for applying for funding calls from the Spanish government. Moreover, during this period I directed two master theses involving the role of CD300f in demyelination and a PhD thesis in the role of CD200R1. Finally, this fellowship allowed me a successful reintegration as I currently hold a Tenure lecture position at the host institution.