Immunological mechanisms underlying sterile inflammation in the pathogenesis of atherosclerosis: potential sites for intervention

ABSTRACT

Introduction: Innate and adaptive immunity play a critical role in the underlying pathological mechanisms of atherosclerosis and potential target sites of sterile inflammation open opportunities to develop novel therapeutics. In response to oxidized LDL in the intimal layer, T cell subsets are recruited and activated at the site of atheroma to upregulate pro-atherogenic cytokines which exacerbate plaque formation instability.

Areas covered: A systematic search of PubMed and the Web of Science was performed between January 2001- September 2020 and relevant articles in sterile inflammation and atherosclerosis were critically reviewed. The original information was collected on the interconnection between danger associated molecular patterns (DAMPs) as the mediators of sterile inflammation and the receptor complex of CD36-TLR4-TLR6 that primes and activates inflammasomes in the pathophysiology of atherosclerosis. Mediators of sterile inflammation are identified to target therapeutic strategies in the management of atherosclerosis.

Expert opinion: Sterile inflammation via NLRP3 inflammasome is perpetuated by the activation of IL-1β and IL-18 and induction of pyroptosis resulting in the release of additional inflammatory cytokines and DAMPs. Challenges with current inhibitors of the NLRP3 inflammasome lie in the specificity, stability, and efficacy in targeting the NLRP3 inflammasome constituents without ameliorating upstream or downstream responses necessary for survival.

KEYWORDS:

• Atherosclerosis
• CD36
• DAMPs
• HMGB1
• inflammasomes
• NLRP3
• oxidized LDL
• pyroptosis
• sterile Inflammation
• toll-like receptors

Article highlights

• Atherosclerosis is a complicated disease mediated by the innate and adaptive immune response. Macrophages express CD36 to facilitate ox-LDL uptake leading to the release of danger associated molecular patterns (DAMPs). ‘Intermediate’ monocytes which express high levels of CD14 and intermediate CD16 have been associated with cardiovascular death.

• Atherosclerosis was described as a Th1 dominant disease whereby IL-2, interferon-γ, and TNF-α has led to upregulation of atheroma formation. Th2 and Th17 have pro-atherogenic and anti-atherogenic effects. Tregs are protective of atherosclerosis.

• Recent research has focused on the triggers of sterile inflammation and the activation of the NLRP3 inflammasome driving atheroma formation.

• HMGB1 and S100 proteins are DAMPs release from damaged cells or immune cells trigger cascade of inflammatory response via binding TLR4, RAGE, and CD36. HMGB1 and S100 proteins drive atherosclerosis through CD36-TLR4-TLR6 complex that primes and activates the inflammasome.

• The pro-inflammatory response is further perpetuated by activation of IL-1β and IL-18 leading to pyroptosis and releases inflammatory cytokines.

• The authors critically discussed the recent developments and novel strategies in the management of atherosclerosis by targeting the mediators of sterile inflammation.

Declaration of interest

The authors have no relevant affiliations or financial or non-financial involvement with any organization or entity with financial or non-financial interest or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The research work of DK Agrawal is supported by research grants R01HL144125 and R01HL147662 from the National Institutes of Health, USA. The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.