TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy

Salyan Bhattarai, Qian Li, Jun Ding, Feng Liang, Ekaterina Gusev, Orsolya Lapohos, Gregory J. Fonseca, Eva Kaufmann, Maziar Divangahi and Basil J. Petrof ()
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Salyan Bhattarai: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Qian Li: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Jun Ding: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Feng Liang: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Ekaterina Gusev: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Orsolya Lapohos: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Gregory J. Fonseca: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Eva Kaufmann: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Maziar Divangahi: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre
Basil J. Petrof: Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. We postulate that an evolutionarily ancient protective mechanism against infection, known as trained immunity, drives pathological inflammation in DMD. Here we show that bone marrow-derived macrophages from a murine model of DMD (mdx) exhibit cardinal features of trained immunity, consisting of transcriptional hyperresponsiveness associated with metabolic and epigenetic remodeling. The hyperresponsive phenotype is transmissible by bone marrow transplantation to previously healthy mice and persists for up to 11 weeks post-transplant. Mechanistically, training is induced by muscle extract in vitro. The functional and epigenetic changes in bone marrow-derived macrophages from dystrophic mice are TLR4-dependent. Adoptive transfer experiments further support the TLR4-dependence of trained macrophages homing to damaged muscles from the bone marrow. Collectively, this suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD.

Date: 2022
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DOI: 10.1038/s41467-022-28531-1

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