Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases

Figures & data

Table 1 The Potential Role of Microglia in Hypertension

Model of Hypertension		Treatment Details	Major Findings	Conclusion	References
Animals	Protocol
Male C57BL/6 and CD11b-DTR mice (8–10 weeks old)	Subcutaneous infusion of Ang II (1000 ng/kg/min) or oral administration of L-NAME (1.5 ng/mL in drinking water) for 4 weeks	DT ICV (1000 pg/g/d) to CD11b-DTR mice	The loss of microglia led to downregulated IL-1β and TNF-α expression in the CNS and decreased the levels of plasma vasopressin, kidney NE, and NMDA.	Microglia are the major cellular factors involved in neuroinflammation and BP regulation.	[32]
Male C57BL/6 mice (12–16 weeks old)	Implanted subcutaneously with a DOCA-silicone sheet (DOCA 1 mg/g body weight) and receiving 1% NaCl drinking water	1. Kinin B1 receptor knockout; 2. R715, a specific B1R antagonist (70 µg/kg/day)	1. DOCA administration upregulated the expression of Kinin B1R in the PVN and RVLM. 2. Kinin B1R deletion or blockade decreased BP, attenuated neuroinflammation and oxidative stress, and restored autonomic function.	Kinin B1R blockade may represent a novel strategy to reduce neuro-inflammation, oxidative stress, and sympatho-excitation in neurogenic hypertension.	[47]
Male C57BL/6J mice (10 months old, 30–35 g)	1. Infusion of Ang II (0.5 ng/kg/day in 9% NaCl) via an osmotic mini pump. 2. TREM2 overexpression in vitro	None.	1. Ang II induced hypertension exacerbated β-amyloid deposition and neuronal apoptosis, increased the number of activated microglia in the cortex and hippocampus of mice, and upregulated microglia TREM2. 2. TREM2 overexpression reversed M1 microglia-induced neuronal toxicity and decreased neuroinflammation.	1. TREM2 plays an anti-neuroinflammatory role in microglia. 2. Controversy remains regarding whether TREM2 participates in the regulation of BP.	[55]
Male C57BL/6 mice (25±5 g)	Electric foot shock with noises induced a stressed condition	RAGE knockout via Cre-CX3CR1/RAGE^fl/fl mice	1. Stress exposure increased the cytoplasmic translocation of HMGB1 in microglia. 2. Microglia-specific knockout of RAGE decreased M1 phenotypic polarization, MAP and sympathetic activities.	Reducing neuroinflammation and SNS activity is associated with BP regulation	[57]
Male C57BL/6, CD11b-DTR and CX3CR1-GFP mice (8–10 weeks old)	ICV infusion of Ang II (500 ng/kg/min)	ICV infusion of a TGF-β neutralizing antibody (50 μg/day), recombinant TGF-β1 (50 ng/day), or DT (800 pg/g BW/day)	1. Blockade of TGF-β signaling further increased BP in Ang II-treated mice. 2. The recombinant TGFβ1 treatment reversed the increased levels of MHC-II and TNF-α, reduced BP reduction, and upregulated the expression of pSMAD 2/3 and COX-2.	Surveillant microglia are tightly regulated by TGFβ, which are critical for maintaining the homeostasis of the CNS and blood pressure.	[58]
Male Wistar–Kyoto rats and SHR rats (6 months old, 200–230 g)	Spontaneously hypertensive rats	Gavage of calcitriol (100 ng/kg)	Calcitriol treatment had no significant effect on BP regulation but it significantly decreased the number of Iba-1^+ cells and levels of IL-1β and TNFα, and shifted microglia polarization from the M1 to M2 phenotype	VitD is neuroprotective in the hypertensive brain by modulating the brain ACE2/Ang(1–7)/MasR axis	[60]
Male Wistar-Kyoto rats and SHRs (7–8 weeks old, 175–225 g)	Spontaneously hypertensive rats	Intraperitoneal (i.p.) administration of the TLR4 antagonist TAK-242 (2 mg/kg/d) for 2 weeks	1. TLR4 inhibition abolished microglia activation and preserved the BBB integrity in the PVN, RVLM, and NTS of SHRs. 2. TLR4 blockade attenuated the progression of MAP increases in SHRs and protected against autonomic dysfunction.	TLR4 represents a viable alternative target in the treatment of hypertension.	[64]
Male Sprague–Dawley rats (250–280 g); Male SHRs, Wistar-Kyoto rats (6 weeks old)	Subcutaneous infusion of Ang II (200 ng/kg/min).	ICV infusion of CMT-3 (3.5 µg/h)	1. The ICV infusion of CMT-3 decreased the number of microglia and percentage of activated microglia. 2. Microglia inhibition also contributed to reduced expression of IL-1β, TNF-α, and TIMP-1, and decreased MAP.	The link between microglia and certain microbial communities may have implications for the treatment of HTN.	[68]
SHRs and Wistar–Kyoto rats (12 weeks old)	Spontaneously hypertensive rats	Aerobic training for 5 days/wk, 1 h/day for 2 wks	Short-term aerobic training contributed to the decrease in HR, Iba-1^+ cells, levels of pro-inflammatory cytokines, and the HMGB1 content and CXCR4 signaling in the PVN.	Aerobic training regulates microglia activation and the production of pro-inflammatory cytokines in the presence of hypertension	[72]

Abbreviations: DTR, diphtheria toxin receptor; Ang II, angiotensin II; L-NAME, N(ω)-nitro-L-arginine methyl ester; DT, diphtheria toxin; ICV, intracerebroventricular injection; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor α; CNS, central nervous system; NE, norepinephrine; NMDA, N-methyl-D-aspartate; BP, blood pressure; RVLM, rostral ventrolateral medulla; SHRs, spontaneously hypertensive rats; CMT-3, chemically modified tetracycline-3; TIMP-1, tissue inhibitor of metalloproteinase-1; MAP, mean arterial pressure; HTN, hypertension; CVLM, caudal ventrolateral medulla; RA, renin-angiotensinogen transgenic; AGT, angiotensinogen; AAV, adeno-associated virus; eGFP, enhanced green fluorescent protein; AT1, Ang II type 1; AVP, arginine vasopressin; CX3CR1, C-X3-C motif chemokine receptor 1; sFKN, soluble fractalkine; NTS, nucleus tractus solitarii; IL-6, interleukin-6; DOCA, deoxycorticosterone acetate; TREM2, triggering receptor expressed on monocytes 2; RAGE, advanced glycation end product receptor; HMGB1, high-mobility group Box 1; SNS, sympathetic nervous system; TGF-β, transforming growth factor-β; MHC-II, major histocompatibility complex-II; pSMAD2/3, phosphorylated mothers against decapentaplegic 2/3; COX-2, cyclooxygenase-2; Iba1, ionized calcium-binding adapter molecule 1; VitD, vitamin D; ACE2, angiotensin I-converting enzyme 2; Ang (1–7), angiotensin (1–7); CXCR4, C-X-C chemokine receptor type 4; HR, heart rate; PVN, hypothalamic paraventricular nucleus.

Table 2 The Potential Role of Microglia in Myocardial Infarction and Cardiac I/R Injury

Model of MI or I/R		Treatment Details	Major Findings	Conclusion	References
Animals	Protocol
Male Sprague–Dawley rats	Ligation of the left anterior descending coronary artery	Infusion of minocycline (172 ng/mL, 0.3 μL/h)	1. After 12 weeks, MI contributed to dramatically increased numbers of activated microglia. 2. Minocycline treatment decreased the number of Iba-1^+ and FRA^+ cells in the PVN and the percentage of activated microglia in the PAG and RVLM. 3. No evidence of improved heart function with minocycline.	Inflammation occurs in brain nuclei, and inhibition of microglia activation may not be sufficient to ameliorate cardiac dysfunction.	[76]
Male Sprague–Dawley rats (200–250 g)	Coronary artery ligation	Intraperitoneal (i.p.) administration of the P2X7R antagonist Brilliant Blue-G (BBG, 25 or 50 mg/kg injection per day for 5 days) before surgery	1. Colocalization of P2X7R with Iba-1 in the PVN rather than neurons was observed after MI surgery. 2. BBG application reduced the expression of P2X7R, IL-1β and TNF-α in the PVN, and improved cardiac function by decreasing MAP, HR, IVP and LVEDP, and the LF/HF ratio.	Inhibition of P2X7R activation in the PVN may be an effective method for the current treatment of AMI.	[81]
Male Sprague‒Dawley rats (50–60 days, approximately 280 g)	Coronary artery ligation	PVN microinjection of Mincle siRNA 24 hours prior to MI surgery (250 pmol/50 nL)	1. The upregulation of Mincle receptor, NLRP3/IL-1β pathway were observed post-MI, and IF suggested that the Mincle receptor colocalized with microglia within the PVN. 2. Mincle knockdown decreased the number of Iba-1^+ cells, inhibited the NLRP3/IL-1β pathway in the PVN and reduced RSNA and NE concentrations.	Inhibition of Mincle ameliorates sympathetic hyperactivity meditated by the NLRP3/IL‐1β pathway.	[83]
Male Sprague–Dawley rats (50–60 days, approximately 260 g)	Coronary artery ligation of LAD	Silence the TLR4 gene in microglia of the PVN via a shRNA	1. After MI, TLR4 was activated predominantly in microglia in the PVN, and NF-κB signaling and ROS production were upregulated. 2. TLR4 gene silencing contributed to the decreased levels of NE and RSNA, and induced the downregulation of NF-κB, IL-1β, and TNF-α expression.	Inhibition of TLR4 attenuated sympathoexcitation.	[84]
Sprague–Dawley rats (250–300 g)	Ligation of the LAD for 30 min and reperfusion for 3 h	LED light source (610 nm) illumination	LED illumination significantly inhibited LSG neural activity and decreased microglia activation and the levels of IL-1β, TNF-α and NGF	LED therapy reduced microglia activation and pro-inflammatory cytokine expression after cardiac I/R	[90]

Abbreviations: MI, myocardial infarction; FRA, fos-related antigens; IVP, intraventricular pressure; LVEDP, left ventricular end-diastolic pressure; NLRP3, NOD-like receptor protein 3; RSNA, renal sympathetic nerve activity; TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa-B; LAD, left anterior descending; I/R, ischemia/reperfusion; LED, light emitting diode; NGF, nerve growth factor.

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