The present study indicated that the mechanism underlying the effects of Tianxiangdan Granule on the prevention and treatment of atherosclerosis may be as follows: Tianxiangdan Granule may decrease the expression of the inflammatory cytokines IL‑1β and TNF‑α, and suppress activation of the NF‑κB p65 and p38 MAPK signaling pathways.
Targeting the IL-1β pathway has already been successful with canakinumab but its expense and inconvenience of administration may limit its widespread uptake for controlling inflammation in atherosclerosis.
Interestingly, IL-1β which is associated to several steps in the development of atherosclerosis, heart disease, and the association of obesity and type II diabetes with CVD, is activated by the inflammasome complex, a multiprotein complex composed of an intracellular sensor, typically a Nod-like receptor (NLR), the precursor procaspase-1, and the adaptor ASC (apoptosis-associated speck-like protein containing a CARD.
It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1β and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability.
Animal studies have further suggested that alterations in the balance between agonists and antagonists of IL-1β are important in promoting atherosclerosis.
IL-1 (interleukin 1) has an established role in atherosclerosis and inflammation, although whether IL-1 inhibition modulates blood pressure is unclear.
IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment.
The successful results of a recent randomized controlled clinical trial targeting inflammasome with anti-IL1β monoclonal antibody in non-autoimmune conditions, prove that specific immunotherapy can be a promising and effective strategy to control atherosclerosis in rheumatic diseases as well.
Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis.
By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis.
Diacerein may have therapeutic applications to diminish IL-1-induced skin inflammation in psoriasis and attenuate IL-1-induced development of atherosclerosis.
Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1β expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.
However, upstream inhibition of CC-induced inflammation by using a complement inhibitor may be more efficient in treating atherosclerosis since this will block initiation of inflammation processes before downstream release of cytokines including IL-1β.
Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis.
Increased plasma levels of IL-1β and IL-18, aggravated macrophage infiltration into atherosclerotic lesions, and accelerated development of atherosclerosis were detected in HHcy mice as compared with control mice, and were associated with the activation of NLRP3 inflammasomes.
We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.
The IL-1β-induced inflammation-activated endothelial cell (EC)-smooth muscle cell (SMC)-mononuclear cell (MC) co-culture model was established, based on the changes in a series of atherosclerosis-associated inflammatory markers secreted by ECs and SMCs.
Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1β, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1β for secretion.
These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1β.
Moreover, the transcripts of interleukin 1 beta (IL-1β) and tumor necrosis factor α (TNFα), which are related to atherosclerosis, were up-regulated by TCDD stimulation.
Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE-/- mice.