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    Home > Biochemistry News > Biotechnology News > TLR4 is a regulator of trained immunity in Duchenne muscular dystrophy

    TLR4 is a regulator of trained immunity in Duchenne muscular dystrophy

    • Last Update: 2022-05-24
    • Source: Internet
    • Author: User
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    Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that affects approximately 1 in 5,000 men
    Despite recent advances in cell- and gene-based therapies, DMD remains a devastating disease with limited treatment options

    The main cause of the disease is the absence of dystrophin, a protein that provides mechanical stability of the sarcolemma by linking the muscle cell's internal cytoskeleton and the extracellular matrix

    Furthermore, macrophages are the most abundant leukocyte population in DMD muscle, and their abnormal persistence and abnormal production of inflammatory mediators play a key role in driving disease progression


    In a previous study, the researchers constructed dystrophic mice (mdx mice, a DMD model) lacking the chemokine receptor CCR2 and demonstrated that bone marrow (monocyte)-derived macrophages (BMDMs) in the early stages of disease importance in pathogenesis
    Genetic ablation of Toll-like receptor 4 (TLR4) in mdx mice was found to have beneficial effects, making intramuscular macrophages more anti-inflammatory

    However, the cellular mechanisms underlying these phenomena are not fully understood


    The researchers studied the changes in BMDM of dystrophic mdx mice and age-matched wild-type (WT) controls after 7 days of culture under basal conditions and found that multiple pro- and anti-inflammatory genes were present in the BMDM of mdx before skeletal muscle necrosis.
    There was significant basal upregulation, most of which remained to a lesser extent in later stages of fibrosis

    This suggests that macrophage-producing precursor cells in the bone marrow are functionally altered during skeletal muscular dystrophy pathology

    In addition, metabolic changes in mdx BMDM at different disease stages were analyzed

    During the necrotic phase, the basal oxygen consumption rate and the maximum oxygen consumption rate of the mdx BMDM group were significantly reduced compared with the WT group of the same age

    In aged mice, lactate concentrations in the mdx group increased during the necrotic phase and decreased during the fibrotic phase


    The staging of disease progression in mdx BMDM underlying inflammatory state

    To determine whether mdx BMDM exhibited nonspecific amplification of gene transcriptional responses after exposure to allogeneic stimulation, we performed multiple unrelated secondary stimuli (cytokines, PAMPs/DAMPs)
    The data demonstrate that after chronic systemic skeletal muscle necrosis in mdx mice, the BMDM is substantially altered, showing marked hyperresponsiveness to multiple unrelated inflammatory stimuli

    In addition, muscle injury-related molecules such as skeletal muscle pulverized extract, fibrinogen can serve as the main "training stimuli" for training immune induction in mdx mouse BMDM


    Further studies found that the hyperresponsiveness to unrelated secondary inflammatory stimuli and the altered metabolic phenotype observed in mdx BMDM were largely abolished by TLR4 deficiency, indicating that the abnormal expression of BMDM in muscular dystrophy mice Epigenetic and functional traits are TLR4-dependent
    In addition, alterations in the BMDM phenotype of mice exhibited hallmark features of trained immunity, including the transmissibility and persistence of immunity that occurred after bone marrow transplantation into non-dystrophic mice

    Therefore, training immunity may be an important mechanism for the generation and maintenance of pathological inflammation in DMD


    Reference: Bhattarai, S.
    , Li, Q.
    , Ding, J.
    et al.
    TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy.
    Nat Commun 13, 879 (2022).
    https://doi .

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