How does dysregulation of DNA sensing cause the autoinflammatory syndrome SAVI?

Kimble, Joshua and Unterholzner, Leonie and Jackson-Jones, Lucy (2023) How does dysregulation of DNA sensing cause the autoinflammatory syndrome SAVI? Masters thesis, Lancaster University.

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Abstract

STING was initially thought to be an adaptor protein with its sole role dependent on pattern recognition receptor (PRR) detection of cytosolic double stranded DNA leading to IRF3 driven canonical pathway activation. However, more recent research demonstrates STING as a signalling hub also capable of activation downstream of DNA damage. DNA damage induces a proinflammatory noncanonical STING response primarily through NF-κB. NF-κB promotes DNA damage repair or cell senescence and clearing however, is associated with autoinflammatory diseases when unregulated. STING-associated vasculopathy with onset in infancy (SAVI) is a rare yet severe autoinflammatory disease initially thought to be caused by hyperactivation of the canonical STING pathway, but knockout of signalling components in mice with the disease did not change its severity or outcome. To investigate the signalling cascades responsible for hyperactivation of the innate immune system, STING-deficient human HaCaT keratinocytes have been reconstituted with the SAVI inducing STING V155M mutant. Analysis of these SAVI-STING cells revealed constitutive hyperactivation of proinflammatory cytokines such as CCL2, CCL20, and IL-6 that are primarily associated with the non-canonical STING pathway, and further activation upon etoposide-induced DNA damage. H-151 induced STING inhibition downregulated proinflammatory cytokine expression, confirming the STING V155M mutant was responsible for the proinflammatory signalling profile, providing insight into the pathophysiology of SAVI patients.