TLR4 is a regulator of trained immunity in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that affects approximately 1 in 5,000 men

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

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.

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)

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

Reference: Bhattarai, S.