Inflammasome Up-Regulation and Activation in Dysferlin-Deficient Skeletal Muscle

Abstract

A deficiency of the dysferlin protein results in limb girdle muscular dystrophy type 2B and Miyoshi myopathy, with resulting plasma membrane abnormalities in myofibers. Many patients show muscle inflammation, but the molecular mechanisms that initiate and perpetuate this inflammation are not well understood. We previously showed abnormal activation of macrophages and hypothesized that activation of the inflammasome pathway may play a role in disease progression. To test this, we studied the inflammasome molecular platform in dysferlin-deficient human and mouse muscle. Consistent with our model, components of the NACHT, LRR and PYD-containing proteins (NALP)-3 inflammasome pathway were specifically up-regulated and activated in dysferlin-deficient but not in dystrophin-deficient and normal muscle. We demonstrate for the first time that normal primary skeletal muscle cells are capable of secreting IL-1beta in response to combined treatment with lipopolysaccharide and the P2X7 receptor agonist, benzylated ATP, suggesting that not only immune cells but also muscle cells can actively participate in inflammasome formation. In addition, we show that dysferlin-deficient primary muscle cells express toll-like receptors (TLRs; TLR-2 and TLR-4) and can efficiently produce IL-1beta in response to lipopolysaccharide and benzylated ATP. These data indicate that skeletal muscle is an active contributor of IL-1beta and strategies that interfere with this pathway may be therapeutically useful for patients with limb girdle muscular dystrophy type 2B.

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

“…It is enigmatic that dysferlinopathy triggers a prominent inflammatory response, but recent findings have revealed some potential causes. Dysferlindeficient monocytes from SJL/J mice were reported to have increased phagocytic activity (26), and dysferlin deficiency induces an upregulation of inflammasome (27). However, a more recent study (18) did not find a difference in phagocytic activity of dysferlindeficient monocytes using C57BL/10-SJL.Dysf mice, which have a more controlled genetic background.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…For example, inflammasomemediated IL-1b overproduction is involved in the pathogenesis of type 2 diabetes, liver damage and muscular dystrophy. [132][133][134] Inflammasome-mediated processes were also observed in cancer, but the association between the inflammasome/IL-1b axis and cancer development is ambiguous. In some studies the inflammasome seems to promote inflammation-mediated tumor development, also confirmed in lung mesotheliomas caused by silica and asbestos.…”

Dysferlin stabilizes stress-induced Ca 2+ signaling in the transverse tubule membrane

“…Dysferlinopathies are associated with increased myofiber necrosis and enhanced immune and inflammatory responses, gauged by increased monocyte and macrophage infiltration (28,29). Previously, we reported that impaired recovery of contractile torque following large-strain injury (LSI) in dysferlin-null mice was concurrent with an increase in necrosis and macrophage infiltration (19).…”