Monocytes and tissue-resident macrophages are crucial for responding to both acute and chronic inflammatory states. Our research group has identified three populations of skeletal muscle-resident myelomonocytic cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1) and T cell membrane protein 4 (TIM4), a population of LYVE1-TIM4- macrophages, and a population of cells positive for CD11C and major histocompatibility complex class II (MHCII). Using a combination of parabiosis and lineage-tracing experiments, we found that, at steady state, TIM4- macrophages were replenished from the blood, whereas TIM4+ macrophages locally self-renewed [self-renewing resident macrophages (SRRMs)]. We found that in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, depletion of both TIM4-- and TIM4+-resident macrophage populations through long-term treatment with two colony stimulating factor 1 inhibitors (CSF1Ri) changed muscle fiber composition from damage-sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative fibers, thereby protecting muscle against contraction-induced injury. This work may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.
Monocytes and tissue-resident macrophages are crucial for responding to both acute and chronic inflammatory states. Our research group has identified three populations of skeletal muscle-resident myelomonocytic cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1) and T cell membrane protein 4 (TIM4), a population of LYVE1-TIM4- macrophages, and a population of cells positive for CD11C and major histocompatibility complex class II (MHCII). Using a combination of parabiosis and lineage-tracing experiments, we found that, at steady state, TIM4- macrophages were replenished from the blood, whereas TIM4+ macrophages locally self-renewed [self-renewing resident macrophages (SRRMs)]. We found that in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, depletion of both TIM4-- and TIM4+-resident macrophage populations through long-term treatment with two colony stimulating factor 1 inhibitors (CSF1Ri) changed muscle fiber composition from damage-sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative fibers, thereby protecting muscle against contraction-induced injury. This work may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.
CSF1R inhibitors as a potential treatment for Duchenne Muscular Dystrophy: in vivo experiments in the mdx murine model
CORDELLA, GIULIA
2022/2023
Abstract
Monocytes and tissue-resident macrophages are crucial for responding to both acute and chronic inflammatory states. Our research group has identified three populations of skeletal muscle-resident myelomonocytic cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1) and T cell membrane protein 4 (TIM4), a population of LYVE1-TIM4- macrophages, and a population of cells positive for CD11C and major histocompatibility complex class II (MHCII). Using a combination of parabiosis and lineage-tracing experiments, we found that, at steady state, TIM4- macrophages were replenished from the blood, whereas TIM4+ macrophages locally self-renewed [self-renewing resident macrophages (SRRMs)]. We found that in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, depletion of both TIM4-- and TIM4+-resident macrophage populations through long-term treatment with two colony stimulating factor 1 inhibitors (CSF1Ri) changed muscle fiber composition from damage-sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative fibers, thereby protecting muscle against contraction-induced injury. This work may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/61192