Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model


Werner syndrome (WS) is a genetic disorder characterized by premature aging and increased susceptibility to age-related diseases such as atherosclerosis. Recent research has shed light on the role of retrotransposons in WS, particularly how they trigger type I interferon-dependent inflammation in macrophages, which are key players in the development of atherosclerosis.

Retrotransposons are DNA sequences that can change their position within the genome, and their activity is generally kept under strict control by various cellular mechanisms. However, in WS-derived macrophages, these control mechanisms are often compromised due to the defective RecQ helicase protein (WRN) that is central to WS pathology. This defect leads to genomic instability and aberrant activation of retrotransposons.

When these retrotransposons become active, they can be transcribed into RNA and further processed into double-stranded RNA (dsRNA), which is typically recognized by the immune system as an indicator of viral infection. This recognition is mediated through pattern recognition receptors (PRRs) that detect dsRNA and subsequently activate signaling pathways leading to the production of type I interferons. These interferons play a crucial role in orchestrating an immune response but can also induce chronic inflammation if their signaling is prolonged or dysregulated.

In the context of atherosclerosis, chronic inflammation driven by type I interferons can exacerbate disease progression. Atherosclerotic plaques, which are formed by the accumulation of lipids and immune cells like macrophages in arterial walls, become more unstable and prone to rupture under inflammatory conditions. The secretion of inflammatory cytokines and other mediators by type I interferon-activated macrophages contributes to this instability.

Research involving WS-derived macrophages has demonstrated that controlling retrotransposon activity through genetic or pharmacological means can reduce type I interferon production and mitigate inflammation. This suggests potential therapeutic avenues for managing both WS-related premature aging and its associated comorbidities like atherosclerosis.

In conclusion, the activation of retrotransposons in Werner syndrome-derived macrophages triggers a type I interferon-dependent inflammatory response that exacerbates atherosclerosis. Understanding this pathway opens up new strategies for therapeutic intervention aimed at reducing chronic inflammation and improving outcomes for patients suffering from WS and possibly other disorders involving dysregulated immune responses.


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