Article Type : Short commentary
Authors : Jiaxin Z, Libo L, Zhenyun Y, Caili H, Jie Y and Sha H
Keywords : Cerebral small vessel disease; Inflammatory response; Inflammatory factors; Atherosclerosis; Immune cells
Cerebral Small Vessel Disease (CSVD) is not only a single
disease, but a kind of clinical and pathological syndrome caused by various
factors, such as intracranial arterioles, perforating arteries and venules,
which can result in structural and functional changes. CSVD accounts for about
25% of ischemic stroke. It is related to cognitive dysfunction, emotional
disorder and even defecation disorder in the elderly, which seriously affects
the quality of life. The clinical manifestations and prognosis that different
patients suffer from are different. The reasons why some patients’ clinical
symptoms are differ from others’ are that besides stroke location, stroke area
and other factors we talked about usually, in addition, inflammatory immune
response also plays an significant role in CSVD. Inflammatory response is a
defense mechanism for us, so that we can respond to a variety of stimulating
factors quickly, by causing a series of effects such as activating inflammatory
cells to release inflammatory factors and other bioactive substances.
Similarly, the immune system of our body is composed of a variety of immune
organs and immune cells, which has the functions of immune defense and immune
regulation. Inflammatory immune response occurs in all systems of the body,
which is regulated by immune cells, inflammatory factors and other mediators,
and plays an important role in the occurrence and development of diseases.
Cerebral Small Vessel Disease (CSVD) is a
disease involving a series of dynamic, whole brain and whole vascular diseases
caused by a number of pathological and imaging changes of intracranial small
vessels caused by many different causes [1,2]. CSVD is short of typical
clinical symptoms in the early stage. However, with the passage of time and the
progression of the disease, recurrent stroke and progressive cognitive decline
which will put patients under great pressure will be the main clinical
manifestations [3-5]. It will mainly cause damage to the subcortical structure
of the brain, characterized by high signal intensity of White Matter Hyper
intensities (WMH), Lacune Infarction (LI), Cerebral Micro bleed (CMB), brain
atrophy and other imaging manifestations [3]. Stroke that is characterized by
high disability rate and other characteristics is divided into haemorrhagic and
ischemic [6]. Studies have shown that when stroke occurs, our brain tissue
quickly responds to ischemia, hypoxia and other stimuli to activate the
inflammatory response, which will further aggravates the brain injury to some
extent, and the brain damage caused by these inflammatory changes even exceeds
the ischemia itself. Besides, the inflammatory reaction is not limited to the
ischemic site, but develops and spreads to the whole brain tissue and exists
for a long time, causing and aggravating the brain tissue injury, which is
closely related to the improvement and recovery of the injured brain tissue
[7-9]. CSVD can be divided into the following types:1) Iatherosclerotic (also
known as age-related)CSVD;2)II ,hereditary/sporadic CAA(Cerebral Amyloid
Angiopathy, CAA); 3)Except for CAA, other hereditary CSVD;4)CSVD related to
inflammation and immunity; 5)CSVD related to inflammation and immunity CSVD; 6)Other
CSVD. Among all the types we list above, ? and ? are the most common in the
clinical. At present, the pathogenesis of cerebral microvascular disease is not
completely clear. In addition to the core mechanism of blood-brain barrier
damage and vascular endothelial dysfunction which are more familiar to us,
inflammatory reaction, immune factors, radioactive factors, heredity, A?protein
deposition, oxidative stress and other factors that play a role in changing the
structure and function of blood vessel wall and vascular reactivity can
indirectly cause vascular endothelial injury and increase the permeability of
blood-brain barrier, which will promote the occurrence and development of
cerebrovascular disease eventually [10-16]. The influence of inflammatory
immune response on the occurrence and development of cerebral microvascular
disease has been further recognized. By releasing inflammatory factors, the
inflammatory-immune response in the brain will inevitably lead to changes in
vascular endothelial structure, and damage the blood-brain barrier, increase
the permeability of blood vessels to harmful substances, and accelerate
intracranial arteriosclerosis. At the same time, inflammatory factors can
directly lead to vascular wall damage, vascular reactivity changes, and damage
its self-regulation function, thus promoting the occurrence and development of
cerebrovascular disease [17]. In this paper, the relationship between
inflammatory immune reaction and cerebrovascular disease (mainly type ? and
type ?) is summarized as follows, in order to better understand the role of
inflammatory immunity in its pathogenesis and lay a foundation for early
prevention and treatment of cerebral small vascular disease [18-20].
Inflammatory factors and aCSVD
Atherosclerotic Cerebral
Small Vessel Disease (aCSVD) is a common type compared with others, while its
pathogenesis is not completely clear. Clinically, it is not difficult to find
that some patients suffered with CSVD who do not have vascular risk factors
such as senility, blood pressure variability, hyperlipidaemia,
hyperhomocysteinemia and so on, which shows routine risk factors are not enough
to fully explain the overall burden of atherosclerosis. Studies have shown that
atherosclerosis is closely related to the drive of inflammatory response. The
release of inflammatory factors and bioactive mediators also plays an important
role in many stages of the pathological process of atherosclerosis, such as
foam cell formation, plaque formation, thrombosis and so on. It is interesting
for to find that infection is not limited to vascular damage caused by
intracranial inflammation, but peripheral inflammation can also migrate and
release inflammatory factors, directly or indirectly aggravating
atherosclerosis [22,23]. As early as the 1980s,Professor ROSS first defined the
concept that atherosclerosis is a kind of chronic inflammation, which has been
widely concerned and recognized by experts and scholars, and has made important
and fruitful achievements in related research fields. Atherosclerosis is
closely related to vascular endothelial cell dysfunction, which is not only a
pathological change of vascular wall in response to various stimulating factors,
but also an important pathophysiological basis of ischemic
cardio-cerebrovascular diseases and an independent risk factor. Studies have
shown atherosclerosis has the remarkable characteristics of inflammatory
reaction such as metamorphism, exudation and hyperplasia, which exists in all
stages of the process of atherosclerosis and is related to the occurrence,
development and prognosis of the diseases caused by atherosclerosis. In the
process of inflammation, it will be accompanied by the activation of many
inflammatory cells, so a large number of serum biological inflammatory markers,
growth factors and adhesion molecules will be released. For example, tumor
necrosis factor ?, interleukin, lipoprotein a, fibrinogen, C-reactive protein,
all of which can result in vascular endothelial cell injury and blood-brain
barrier damage. Endothelial function and blood-brain barrier dysfunction can
increase the permeability of small vessels, further aggravate the infiltration
of inflammatory cells, and even lead to cerebral microhemorrhage caused by
vascular rupture, which will increase the risk of CSVD [22,23]. In addition, it
can also reduce cerebral blood flow and impaired brain self-regulation
function, which increase the opportunity of cerebral stroke caused by the
lackness of ischemia and anoxia. A cross-sectional study of imaging findings
and risk factors of cerebral microvascular disease shows that long-term
insufficient cerebral blood flow and low cerebral perfusion can lead to chronic
and diffuse subcortical ischemia, which is called white matter damage that is
the most prominent imaging feature of cerebral microvascular disease; Besides
it can cause acute severe local ischemia, named lacunar cerebral
infarction,which adversely affects the quality of life of patients. The
research progress on the relationship between several common inflammatory
factors and atherosclerosis (Atherosclerosis, As) is stated as follows [24,25].
Homocysteine
(Hcy)
Homocysteine is a kind of
amino acid, which is related to the metabolism of vitamin B12, folic acid and
vitamin B6.At the same time, Hcy is an index that can reflect the systemic
inflammatory response, and it is a vascular endothelial inflammatory factor. The
increase of homocysteine in vivo will lead to vascular endothelial damage,
promote the occurrence and progress of atherosclerosis, and is a potential
pathogenic factor for the occurrence of cardio-cerebrovascular diseases [26].
Studies have shown that high levels of Hcy aggravate oxidative stress and are
closely related to the occurrence, progression and overall burden of high
signal intensity in white matter. Another study shows that homocysteine can
induce both of the release of representative inflammatory factor C-reactive
protein and inflammation in the brain, which will cause blood-brain barrier
dysfunction, and lead to vascular lesions of the nervous system eventually
[28,29]. Long-term atherosclerosis is an independent risk factor for the occurrence
of cerebrovascular disease and is closely related to its prognosis. So, to some
extent, inhibiting inflammation by reducing the level of homocysteine may slow
down the progression of cerebrovascular disease.
Interleukin
Interleukin (IL) is a
kind of cytokines secreted by a variety of immune or non-immune cells, which
plays an important role in the process of inflammatory response, immune cell
activation, functional regulation, lymphocyte activation and so on. IL-6
mediates platelet aggregation, C-reactive protein expression and the release of
other inflammatory mediators, which leads to the inflammatory development and
poor reactivity of vascular endothelium [30]. In addition, other studies have
shown that IL-6 may accelerate the decline of mitochondrial function, resulting
in brain tissue hypo perfusion, blood-brain barrier function damage and brain
balance damage. The experimental studies of have shown that IL-1 ? has an
anti-atherosclerotic effect by reducing the expression of inflammatory factors,
achieving the goal that reducing the occurrence of cerebrovascular disease
[31,32]. In recent years, the relationship between new interleukin subtypes
such as IL-18,IL-37,IL-38 and plaque formation and stability has gradually
become clear, and valuable results have been obtained, which has been widely
recognized by people[33,34].IL-18 may be closely related to white matter
lesions, but the relationship between IL and atherosclerosis and imaging
features of cerebral microvascular disease still needs further study, so that
it may provide new theories and ideas for the prevention and treatment of
cerebral microvascular disease.
Tumor
Necrosis Factor (TNF)
Tumor necrosis factor
(TNF) is a key cytokine with multiple functions secreted by peripheral immune
cells such as mononuclear macrophages and neutrophils. A study on the
relationship between cerebral infarction and serum TNF levels shows that TNF
promotes T cell subsets and immune function disorder by directly or indirectly
acting on CD4,CD8 and other immune cells; In addition, Tumor Necrosis Factor
Associated Factors (TRAFs)can also promote the progression of inflammation by
regulating the expression of receptors in the process of inflammation, and they
jointly participate in the inflammatory response, which can accelerate the
progression of cerebral atherosclerosis [9,35,36]. Both of long-term
atherosclerosis and even thrombosis can lead to insufficient cerebral blood
flow, and low perfusion of brain tissue which will promote the progression of
cerebrovascular disease. In addition, other studies suggest that there is a
correlation between TNF and CSVD imaging findings proposed for the first time
that patients with CMB have higher levels of serum TNF, while according to the
relationship between TNF and lacunar infarction and high signal intensity of
white matter, it is not completely clear, so much more researches are needed to
explore the relevance between them [37,38].
Matrix
metalloproteinases (MMP)
Matrix metalloproteinase
(MMP) is a biomarker of endothelial injury mediated by extracellular matrix
metalloproteinase inducer (EMMPRIN) on the surface of many kinds of cell
membranes [39,40]. MMP is a large family, among which MMP-2, MMP-3, MMP-9 is
the most widely distributed in the brain. The biological factors secreted by
MMP-2, MMP-3, MMP-9 may mediate inflammation and damage the function of
blood-brain barrier [41]. Therefore, inhibiting the release of various
inflammatory factors from MMP would be an effective and ideal target for new
drug development. In addition, other studies have shown that MMP hydrolyzes the
proteins of the basement membrane, which is the key structure of the
blood-brain barrier, and degrades the extracellular matrix to make it
dysfunctional, resulting in the increase of the permeability of the blood-brain
barrier and the entry of lipids and proteins into the brain parenchyma,
resulting in brain damage [42]. MMP causes small vascular endothelial
dysfunction through a variety of ways, such a through resulting in increased
permeability, promoting blood-brain barrier damage and brain tissue damage,
resulting in the occurrence of cerebrovascular disease finally. A study
reported on the relationship between MMP-9 and mild cognitive impairment in
patients with OSA showed that MMP was associated with WMH load, an imaging
marker of cerebrovascular disease [43]. Some studies have shown that MMP-9 may
be associated with hypertensive intracerebral hemorrhage and spontaneous
cerebral microhemorrhage by increasing oxidative stress, but it is not
completely clear so far [44]. An study based on animal model has found that
inhibition of EMMPRIN can reduce brain injury and inflammatory response after
stroke, which may promote the recovery of neurological function, which is hoped
to become a new target for the treatment of cerebral microvascular disease
[45,46]. According to the conclusion of Paritzz, basing on the concentration
and expression characteristics of EMMPRIN in serum, we may can use EMMPRIN as a
new biomarker to predict the prognosis of stroke patients. Through the
intervention of MMP and its inducible regulatory factors, it may become a new
strategy for the prevention and treatment of cerebrovascular diseases. At
present, the research on the relationship between serum inflammatory factors
and cerebrovascular disease is still absolutely unclear. In the future, it is
hoped that more studies will start from many aspects and dimensions, such as
the related pathological process of serum inflammatory factors and
cerebrovascular disease, iconic imaging changes, cognitive dysfunction after
stroke caused by cerebral microvascular disease, post-stroke emotional disorder
and so on to explore the pathogenesis of cerebrovascular disease. Standing on
great findings, we may provide strong help for patients who are suffered with
cerebral small vessel disease to lighten the burden of economy, life and
society.
Immune
response and aCSVD
The immune system of the
body is a huge and complex system. When the body is stimulated by external
stimuli or abnormal changes in itself, expect for the occurrence of
inflammatory reaction, the activation of the immune system also plays an
important role, and the two complement each other to aggravate brain injury and
promote the occurrence and development of cerebrovascular disease[47,48].With
the rapid development of modern science and technology, the influence of immune
response in cerebral microvascular disease has gradually been widely concerned
by scholars and achieved fruitful results. Immune responses include congenital
and adaptive. Physical barrier and mononuclear macrophages, neutrophils,
natural killer cells, chromophilic granulocytes, dendritic cells and other
cells constitute the innate immune system, while the adaptive immune system is
divided into T-lymphocyte-mediated cellular immunity and B-lymphocyte-mediated
humoral immunity [49,50]. What is discussed below is a brief introduction about
the study of neutrophils, iymphocytes and atherosclerotic cerebrovascular
disease.
Neutrophils
and aCSVD
Neutrophils relying on
their strong chemotaxis and phagocytosis become an important factor in acute
inflammation and innate immunity, and play an important role in various
processes of atherosclerosis [51]. The basis of vascular pathological changes
is endothelial damage, which can quickly activate inflammatory cells to release
a variety of inflammatory mediators with different functions to produce
inflammatory response. Neutrophils are closely related to the occurrence,
progression and outcome of inflammatory response [52]. Studies have shown that
neutrophils and myeloperoxidase and other biomarkers stored in them cause
vascular endothelial injury, adverse interaction between inflammatory cells and
endothelial cells, and enzymatic hydrolysis of extracellular matrix through a
series of pathological processes, which may accelerate the formation of
unstable plaques, thrombosis, and promote the occurrence and progress of
atherosclerosis and cerebrovascular diseases [52]. Since an index called
Neutrophil extracellular traps (NET) was put forward in 2004, it has been paid
more and more attention. It may be involved in many pathological processes,
such as inflammatory reaction, oxidative stress, thrombosis and so on, which
may become a new target for treatment [53,54].
Lymphocytes
and aCSVD
Lymphocytes (B
lymphocytes, T lymphocytes) make the body produce immune response through the
process of transformation, production of antibodies and secretion of factors,
which is the key factor of adaptive immune response. T lymphocytes are mainly
composed of two cell subtypes: helper (Th) and cytotoxic (CTL).Different
subtypes of lymphocytes are involved in the occurrence of atherosclerosis by
secreting a variety of functional cytokines [51,55]. They have a two-sided
effect in the process of atherosclerosis. For example,Th1,Th2, Th17 and other
different cells can secrete many kinds of cytokines, such as
interferon-?,IL-2,IL-17 and so on, which promote vascular inflammation, and
cause vascular endothelial dysfunction, blood-brain barrier destruction,
decrease vascular reactivity, all of which will lead to brain tissue hypo
perfusion, and promote the occurrence of cerebral small vascular disease.
Regulatory T cells, as immunosuppressive cells, can inhibit inflammatory
response by remodelling plaques and enhancing their stability, which play a
significant role in slowing down the development of atherosclerosis, and
protecting blood vessels and reducing the occurrence of cerebrovascular
disease. Similarly, B lymphocytes have a dual effect on atherosclerosis
[56-58]. Studies have shown that B1 lymphocytes can produce anti-As IgM
antibody, act on oxidized low density lipoprotein (ox-LDL), which is closely
related to As formation, prevent the release of related inflammatory factors,
endothelial cell injury, plaque formation, and achieve the effect of
anti-atherosclerosis [59,60]. On the contrary, B2 lymphocytes promote the
formation of unstable plaques by secreting IgM antibodies on vascular smooth
muscle cells and increasing the risk of atherosclerosis [51]. In a word, innate
immune cells such as neutrophils and adaptive immune cells dominated by
lymphocytes play an important role in the occurrence and development of as
through different pathological mechanisms. Therefore, two more objective and
comprehensive serum detection indexes called NLR (neutrophil/lymphocyte) and
PLR (platelet/lymphocyte), have attracted more and more attention. These two
indicators take more into account the effect of the balance of immune cell
subsets on as, and the study shows that NLR and PLR have predictive value in
intracranial atherosclerotic stenosis and are related to the degree of
intracranial atherosclerotic stenosis [61-63]. It is familiar to us that
long-term arterial stenosis will lead to a series of brain lesions, such as
insufficient intracranial cerebral blood flow, cerebral ischemia and hypoxia,
endothelial dysfunction, blood-brain barrier damage and so on, all of which
will promote the occurrence of cerebral microvascular diseases finally.
Autoimmune
antibodies and aCSVD
With the deepening of the
study on the vital role of atherosclerosis in the pathogenesis of
cerebrovascular disease, the incidence of cerebrovascular disease in some
autoimmune antibody positive patients is higher [64]. Autoantibodies are
involved in all pathological stages of atherosclerosis. It has been found that
anticardiolipin antibody (ACA) can be used as an independent risk factor for
the occurrence and development of atherosclerosis, although its mechanism needs
further study [65]. Absolutely, the relationship between autoimmune antibodies
commonly used in clinic, such as ANCA, ENA, antinuclear antibody, and
cerebrovascular disease and atherosclerosis needs a large number of studies to
find out in the future. Through the inhibition of autoimmune reaction and inflammatory
reaction, it may provide a new direction for the prevention and treatment of
cerebrovascular disease. In summary, atherosclerosis is a pathological process
characterized by long-term chronic inflammatory reaction. At the same time, the
study of the relationship between autoantibodies and it is gradually clear.
Inflammation and autoantibodies are involved in all stages of its development
and affect its prognosis. As the most common cerebrovascular disease, it is
particularly important for the prevention and treatment of aCSVD. Inflammation
and immune response play an important role in the formation and progression of
atherosclerosis. Therefore, by detecting the level of related antibodies and
inhibiting the release of related inflammatory factors, we can achieve early
prevention and treatment of atherosclerosis and slow down the progress of As,
so as to provide a new direction for the treatment of cerebrovascular diseases
such as atherosclerosis, cerebrovascular disease and stroke, and make it beneficial
for more and more patients.
Inflammatory
Reaction and Cerebral Amyloidosis
Cerebral amyloidosis (CAA) is another common
type of cerebral microvascular disease. The main pathological manifestation is
the deposition of A? protein in the vascular wall of the brain, which is a
common intracranial vascular disease in the elderly. The balance of A? protein
in the brain is maintained by enzymatic hydrolysis or internal and external
transport of the blood-brain barrier. When the excessive deposition of A? protein
exceeds the clearance capacity of the enzyme, and the transport capacity of the
blood-brain barrier is decreased due to various reasons, the abnormal
accumulation of A? protein produces CAA [66]. CAA is an important cause of
spontaneous and recurrent cerebral lobe micro haemorrhage, especially occipital
lobe haemorrhage in the elderly. In addition, strictly speaking, cerebral micro
haemorrhage is associated with cognitive impairment. Therefore, as an important
cause of lobar micro haemorrhage, CAA may be an important cause of cognitive
impairment in the elderly [2,67]. As another common type of cerebrovascular
disease, the study on the relationship between inflammatory factor secretion,
immune system activation and CAA is also of great value. It is absolutely
necessary to further explore the role of inflammatory immune response in the
process of CAA, so as to improve the life and health of the people who are
suffered with it. Presently, the research on the relationship between immune
response and CAA is not supported by a large number of data, so further
research is needed to provide a new method for the effective prevention and
treatment of cerebral microvascular diseases. To sum up, with the rapid
development of economy, the progress of medicine and the change of population
structure in China, post-stroke cognitive impairment and post-stroke depression
caused by cerebral microvascular disease have brought great burden to
individuals and society. More and more evidence supports that the detection
indexes of serum inflammatory factors, inflammatory reaction and autoimmune
related antibodies are closely related to the occurrence, progression and
prognosis of cerebrovascular disease and atherosclerosis (lipid stripes, plaque
formation, thrombosis and other pathological processes),but its pathogenic
mechanism is not completely clear. At present, the treatment of cerebral
microvascular diseases is mainly anti-platelet aggregation, lipid-lowering
plaque and other conventional stroke treatment, and its prevention focuses on
bad lifestyle changes. Therefore, there is more and more consensus on the early
detection of a new direction for the prevention and treatment of
cerebrovascular diseases. The serum indexes such as inflammatory factors and
autoimmune antibodies are easy to obtain and economical in clinic, and it is
particularly important to study the correlation between them and
cerebrovascular diseases. Through the detection of these serum indexes, we can
better and more quickly screen out the high-risk population of cerebral small
vascular disease and make early intervention, so that we may provide a new
strategy for the early diagnosis and treatment of cerebral small vascular
disease.