Fight Aging!

In the progression of degenerative aging, a process of constant, unresolved inflammatory signaling is one of the most important ways in which low-level molecular damage gives rise to widespread dysfunction of tissue and organs. In today's open access paper, researchers discuss what is known of the way in which the innate immune system reacts to molecular signs of aging, the damage-associated molecular patterns such as DNA debris from dysfunctional mitochondrial and stressed and dying cells. This reaction is amplified by the rest of the immune system into a constant, disruptive state of chronic inflammation that changes cell behavior for the worse and degrades tissue structure and function.

Certain common mechanisms of signaling and regulation, such as the better studied forms of inflammasome, are interesting targets for those seeking to develop therapies to effectively suppress inflammation. The challenge in such efforts has always been to suppress inflammatory signaling in a way that only interferes in excessive inflammation, and not the necessary inflammation required for defense against pathogens, regeneration following injury, and so forth. Existing therapies, such as the biologics used to treat autoimmune conditions, tend to focus on inhibition of specific single signal molecules involved in the inflammatory process, and thus indiscriminately suppress inflammation. There is some hope that targeting inflammasomes will prove to be a better option.

The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection

An inflammasome is a multiple protein complex, comprised of sensor proteins such as pattern recognition receptors (PRRs), an effector protein (i.e., caspase-1 in canonical inflammasome, and an adaptor protein (i.e., apoptosis-associated speck-like protein, ASC, containing a caspase activation and recruitment domain, CARD). An inflammasome modulates the innate immune signaling where PRRs respond to pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs), which results in the activation and accumulation of caspase-1 that cleaves pro-interleukin (IL)-1β and pro-interleukin (IL)-18 to their active forms. The activated pro-inflammatory cytokines modulate inflammation in a series of disorders, including chronic inflammatory disease and neurodegenerative disease.

The pathophysiological basis of cerebral small vessel disease (CSVD) involves changes in the structure and function of cerebral microvasculature that penetrates in deep subcortical regions, such as arteries and/or arterioles as well as lipohyalinosis, microthrombosis, necrosis, and fibrinolysis. CSVD is common with aging and is frequently discovered as an incidental finding after neuroimaging. It is often overlooked by physicians due to its covert nature (i.e., asymptomatic). The neuroimaging manifestation of CSVD includes white matter hyperintensities (WMHs) of presumed vascular origins, enlarged perivascular spaces (ePVS), lacunar infarcts, cerebral microbleed (CMBs), and cortical microinfarcts. Alarmingly, these manifestations account for approximately 25% of the total global cases of ischemic stroke, and over 70% of vascular dementias.

An increase in systemic inflammatory agents such as IL-1β, IL-6, and C-reactive protein (CRP) plays the most important roles in the genesis of neuroinflammation in CSVD and ischemic stroke. The heightened pro-inflammatory agents alongside endothelial dysfunction (i.e., due to the formation and accumulation of cell-derived microparticles and disrupted purinergic signaling) may further aggravate endothelial injury. For example, microthrombi and/or microparticles may aggregate on the endothelial surface, worsening blood-brain barrier (BBB) permeability and leading to microvascular bleeding. Furthermore, inflammation may disrupt cell-cell interactions, exacerbating the cellular injury that results in luminal narrowing, reduced cerebral blood flow, hypoxia, neuronal cell death, and parenchyma damage.

Following parenchyma injury, sequences of pathological changes that ensue could eventually elicit the activation of the NLRP3 inflammasome. The activated NLRP3 inflammasome may further worsen the parenchyma injury through a cascade of inflammatory signaling. As aforementioned, the NLRP3 inflammasome is crucial in the genesis of atherosclerosis, arteriosclerosis, and arteriolosclerosis and increases the likelihood of CSVD and ischemic stroke. Thus, here we hypothesize plausible pathophysiological mechanisms that underlie the NLRP3 inflammasome-linked CSVD through the NLRP3-mediated neuro-thrombo-inflammation, its influence on disease progression and potential therapeutic target.

In our hypothesis, blood-brain barrier (BBB) breakdown caused by elevated thrombo-inflammation, neuronal injury, and activation of neuroglial cells mediates the mitochondrial dysfunction leading to increased production of reactive oxygen species (ROS). ROS activated the NLRP3 inflammasome leading to pyroptosis and secondary neuronal injury that may lead to the development and progression of cerebral small vessel disease (CSVD). Besides, cellular oxidative stress also causes hypoxia-mediated NF-κB pathway activation that subsequently led to NLRP3 inflammasome activation.