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Gene & Protein in Disease Hematoma clearance by microglia after ICH

like 3 (OLFML3), sialic acid-binding immunoglobulin- anti-inflammatory markers predominate at the injury site
like lectin H (Siglec-H), and G protein-coupled receptor in the chronic stage of ICH (Figure 1) .
[43]
34 (GPR34) are specific markers of stably expressed In early 2003, we reported for the first time that
microglia [32-34] . CD163 and CD44 are general markers microglial activation contributes to endogenous hematoma
of monocyte-derived macrophages that infiltrate the clearance after ICH . Our recent study has demonstrated
[44]
brain, contributing to functional recovery after ICH [34-36] . that improving microglial and macrophage alternative
Through transmission electron microscopy, reactive activation contributes to hematoma absorption and better
phagocytic microglia are identified in the ICH brain, which neurological function, as demonstrated in the hindlimb
[37]
can phagocytose erythrocytes and necrotic neurons . adduction test, the corner turn test, and the forelimb
Microglial phagocytosis markers include CD68, triggering placing test . In addition, microglia promote cell debris
[8]
receptor expressed on myeloid cells 2 (TREM2), galectin-3 and hematoma clearance and reduce harmful cytokine
(GAL-3), and CD11c . More research on these markers production during activation through phenotypic changes
[38]
and their role in the pathogenesis of ICH can generate in the subacute and chronic stages to reduce brain injury and
exciting new findings, such as ICH outcome improvement promote functional recovery after ICH [11,18] . Furthermore,
by inhibiting the expression of pro-inflammatory the cytokines TNF- α, IL-4, IL-6, and IL-10 can reprogram
markers . microglia toward a phagocytic phenotype with improved
[26]
Depending on the different phenotypes, microglia phagocytosis for hematoma clearance [26,38,45] .
play a role in brain injury or repair after ICH . The
[26]
nuclear factor kappa B signaling pathway regulates the 4. Hematoma clearance by reactive
expression of pro-inflammatory mediators in activated microglia: Role of IL-10-mediated pathway
microglia [22,25,39] . Pro-inflammatory microglia produce pro- Previous research has identified certain drugs or molecules
inflammatory cytokines, such as IL-12, IL-1β, IL-6, tumor that can promote the clearance of hematoma, including
necrosis factor alpha (TNF-α), nitric oxide (NO), and Vitamin D, which can stimulate microglia/macrophage
reactive oxygen species (ROS), that contribute to blood- proliferation and differentiation; IL-4, which improves
brain barrier (BBB) rupture and edema formation after STAT6 activation; low-density lipoprotein receptor-1
ICH [10,26,40,41] . In contrast, signal transducer and activator of (LRP1), which promotes heme scavenging through binding
transcription 6 (STAT6) accumulates in response to IL-4 to hemopexin-heme complexes; and IL-10, peroxisome
and promotes anti-inflammatory microglial phenotypic proliferator-activated receptor gamma (PPAR-γ), and
[26]
transformation . Microglia of the anti-inflammatory nuclear factor-erythroid 2 p45-related factor 2 (NRF2),
phenotype produce anti-inflammatory cytokines, such which upregulate CD36 expression [46-49] . Furthermore,
as transforming growth factor beta (TGF-β), IL-4, IL-10, fractalkine (FKN) promotes hematoma absorption
IL-13, extracellular matrix proteins, glucocorticoids, through the PPAR-γ/CD163/hemeoxygenase-1 (HO-
and growth factors . Since these cytokines exhibit anti- 1) signaling pathway in microglia, while PPAR-γ plays a
[22]
inflammatory and neuroprotective properties, they protect protective role through the haptoglobin (HP)-hemoglobin
the BBB and promote brain repair. Due to their ability to (Hb)-CD163 pathway [50,51] . Other strategies that may also
switch between pro-inflammatory and anti-inflammatory be promising for hematoma clearance include the CD47-
phenotypes, activated microglia can regulate the immune blocking antibody, pulsed electromagnetic field (PEMF)
[23]
response according to the microenvironment . Research therapy, intranasal IL-4 treatment, exogenous sulforaphane
has shown that microglial activation occurs within 1 h administration that can activate NRF2, and treatment with
after the onset of ICH , with upregulated expression of plasma kallikrein inhibitor (aprotinin) and PPAR-γ agonist,
[42]
pro-inflammatory cytokines, such as iNOS, IL-6, TNF, and such as monascin, rosiglitazone, and pioglitazone [46,49,51-54] .
IL-1 β, in the first 3 days, followed by a rapid decrease . The phase 2 clinical trial on pioglitazone for hematoma
[7]
Furthermore, markers of the anti-inflammatory phenotype, resolution (ClinicalTrials.gov Identifier: NCT00827892)
such as IL-10, ARG1, CD206, CD163, and YM1, begin to was completed in 2013 but has not released the final
rise on day 1 after ICH, with a change in phenotype from report to date, probably due to negative result. Hence,
pro-inflammatory to anti-inflammatory in the first 7 days. researchers are now focusing on signaling pathways other
From days 7–14, the anti-inflammatory cytokine TGF-β than those involving PPAR-γ, such as IL-10, a critical anti-
is upregulated, while the levels of most pro-inflammatory inflammatory cytokine that could contribute to hematoma
cytokines return to baseline on day 14 (Table 1) . In clearance. Therefore, studying the role and mechanism
[26]
summary, there is a change in microglial phenotype from of action of microglial IL-10 signaling can help identify
the pro-inflammatory phenotype in the acute stage to a new and promising therapeutic strategies for hematoma
mixed phenotype in the subacute stage of ICH. Eventually, clearance after ICH.

Volume 2 Issue 2 (2023) 3 https://doi.org/10.36922/gpd.336