Here, researchers review cellular senescence in macrophage cells and the biochemistry of long non-coding RNAs in macrophage senescence, a topic of great relevance to a number of age-related conditions, such as atherosclerosis. Cellular senescence takes place in most cell populations, in response to reaching the Hayflick limit on replication or in response to stress and damage. Senescent cells have important short-term roles to play, and near all destroy themselves or are destroyed by immune cells soon after entering the senescent state. These cells become harmful when they linger over long term, however, even in comparatively small numbers. They secrete a mix of signals, the senescence-associated secretory phenotype, that encourages other cells to become senescent, rouses the immune system to chronic inflammation, destructively remodels surrounding tissues, and more. The accumulation of senescent cells is one of the driving causes of degenerative aging.
Cellular senescence is a particularly stable state of permanent cell cycle arrest. Macrophages, although terminally differentiated cells, do not undergo this type of replicative senescence and may hence undergo stress-induced senescence. In healthy conditions, macrophages maintain homeostasis; however, in pathological states, different stresses including DNA damage, telomere shortening, oncogene activation, impairment of some key proteins, and infections activate the p53, AIM2, and NF-κB signal pathways, initiating macrophage senescence.
When these damage-associated molecule patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are highly intensive or temporally irreversible, the balance between the production and clearance of proinflammatory factors is disrupted. At later stages of macrophage senescence, the net effect is senescence-associated secretory phenotype (SASP) expression. These factors not only aggravate macrophage senescence but are also extracellularly released, thus impairing the functions of surrounding cells. This process is called "paracrine senescence" and causes a wider range of inflammaging. With steady accumulation of senescent cells, senescence eventually occurs at the cellular level and then at the organ level, causing organ malfunction, consequently resulting in corresponding aging phenotypes.
Emerging data suggest that long non-coding RNA (lncRNA) plays a key role in regulating inflammatory responses. Alterations in various lncRNA expression levels are associated with a proinflammatory phenotype in various age-related diseases (ARDs). This leads to modification of cellular senescence through several diverse approaches, whether by mediating gene expression or protein function or functioning as competing endogenous RNA (ceRNA). Changes in lncRNAs in ARDs and the corresponding consequences have been widely studied, especially in cancer. However, the association between lncRNA and cellular senescence in ARDs remains an interesting and complex issue.
Atherosclerosis is a chronic inflammatory disease. Macrophages have been recently reported to display marked inflammatory plasticity, particularly polarization. They perpetuate chronic inflammation and growth of atherosclerotic plaques, thus being central to the initiation, growth, and ultimately the rupture of arterial plaques. Studies on atherosclerosis and macrophages have reported that lncRNAs majorly function as ceRNA in causing atherosclerosis. By sequestering microRNAs, MITA, GAS5, HOTAIR, and UCA1 promote M1 polarization, inducing proinflammatory cytokine, matrix metalloproteinase, and reactive oxygen species (ROS) levels. Atherosclerosis contributes to various lesions, especially cardiovascular disease. Current evidence suggests that the effect of lncRNAs on macrophages in coronary artery disease is the same as that on atherosclerosis, highlighting the consistency of its function and prompting its potential as a therapeutic target.