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Advanced Neurology Inflammation in diabetic stroke: Pathogenesis

Macrophages and monocytes are key players in stress, neuroinflammation, and autophagy dysfunction
diabetes-accelerated atherosclerosis. Hyperglycemia contribute to the brain ischemic damage in the penumbra,
and insulin resistance impair macrophage efferocytosis which are the potential treatment targets to reduce
and apoptosis, hampering inflammation control and ischemic damage.
atherosclerotic plaque regression. Animal studies have Following an ischemic insult, hypoxia causes
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shown that chronic hyperglycemia and even transient depolarization of mitochondria and energy depletion
intermittent hyperglycemia alone can systemically increase which is followed by extracellular accumulation of
circulating monocytes. 36,37 This was driven by a systemic excitatory glutamate. N-methyl-D-aspartate receptors
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increase in the neutrophil-derived alarmins, S100A8/A9, activated by glutamate trigger the formation of ROS. These
which signals through RAGE to promote myelopoiesis in excessive oxidative species cause lipid peroxidation, protein
the bone marrow. 36,37 Diabetes causes monocytes to assume denaturation, and DNA modification. These molecules
a more inflammatory phenotype, possibly mediated released by the dead and dying cells in the ischemic area
by redox-sensitive mitogen-activated protein kinases are collectively called danger-associated molecule patterns
phosphatase 1. 38
(DAMPs), which can induce inflammatory process. 43
Hyperglycemia also causes platelet hyperactivity.
DAMPs are initially detected by pattern recognition
Glycation of platelet-surface protein impairs its membrane toll-like receptors (TLRs) that are located on the surface
fluidity, resulting in increased adhesion. Hyperleptinemia of microglia. DAMP-TLR binding initiates the NF-κB
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and reduced NO also contribute to the increased platelet signaling pathway, which induces the synthesis of the
adhesion. Hyperglycemia and low-grade inflammation pro-inflammatory cytokines, especially IL-1β. IL-1β
activate platelets by increasing GpIIb/IIIa expression and is synthesized as an inactive precursor, and pro-IL-1β
promoting its translocation to platelet surface, resulting in
prothrombic state. 39 is activated by intracellular protein complexes called
inflammasomes (Figure 2). Inflammasomes are assemblies
Individuals with type 2 diabetes typically live with other of sensor molecules (e.g., NLRP3), pro-inflammatory
comorbidities such as hypertension and hyperlipidemia. caspases (e.g., pro-caspase 1), and adaptor proteins. 44,45
Hypertension increases the risk of the initial endothelial Inflammasomes can detect a variety of deleterious
damage, whereas hyperlipidemia increases the expression signals, such as exogenous infection and internal damage
of adhesion molecules (e.g., VCAM-1) and chemoattractant (e.g., DAMPs), and can activate caspase 1, which then
factors and activates proinflammatory chemokines (e.g., processes pro-IL-1β to its mature form IL-1β. IL-1β
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IL-8) in the artery wall. Furthermore, diabetes exacerbates induces pro-inflammatory microglia (M1 phase) to
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atheroma expansion by increasing macrophage lipid synthesize more IL-1β and other pro-inflammatory
loading and intensifying the inflammation in the plaque, molecules, including IL-6, IL-8, and TNF-α. Animal
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leading to accelerated cell death and the formation of a studies showed that NLRP3 inflammation drives
necrotic core. 38 inflammation in ischemia and reperfusion brain damage. 48
In summary, chronic hyperglycemia and Following initial microglia activation, pro-inflammatory
hyperleptinemia in type 2 diabetes are associated with processes in the ischemic environment attract peripheral
vascular endothelial dysfunction, chronic inflammation, immune cells into the brain parenchyma. Neutrophils are
and oxidative stress, which give rise to vascular dysfunction the first to arrive, contributing to the enlargement of the
and accelerated atherosclerosis (Figure 1). area of ischemic brain injury by worsening oxidative stress
through activating their own iNOS, damaging the blood–
4. Inflammation in acute ischemic stroke brain barrier (BBB) by increasing matrix metalloproteinase
During acute ischemia, the decrease in blood flow is (MMP) expression. Monocytes, attracted by chemokines,
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not uniform. In the ischemic core (blood flow <20%), then enter the damaged area and transform into
the oxygen-glucose deprivation causes a disturbance macrophages. Lymphocytes appear in the ischemic area
in the ATP-dependent K+/Na+ pump, resulting in 24 h after the start of reperfusion and peak at around 7 days,
cytotoxic edema, calcium overload, and mitochondrial contributing to the post-ischemic brain damage. However,
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depolarization, followed by free radical damage in in later stages, with the evolving ischemia and reperfusion,
both neuron and astrocytes, which are irreversible. the pro-inflammatory cells (e.g., microglia, monocyte-
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In the penumbra (∼40% blood flow), a combination of derived macrophages, and monocytes) polarize toward a
excitotoxicity, peri-infarct depolarization, inflammatory protective anti-inflammatory phenotype (M2 phase) due
processes, and vascular injury cause varying degrees of to the release of transforming growth factor beta 1, glial
damage to the NVU. Evidence suggests that oxidative cell-derived neurotrophic factor, and anti-inflammatory
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Volume 3 Issue 2 (2024) 4 doi: 10.36922/an.1683