MiR-29a, miR-29b, and miR-29c were belong to the miR-29 family, and the levels of miR-29a and miR-29b-1 were decreased in AD patients (87). Srivastava et al. (2016) predicted miR-29a could target key members of the TNF-mediated pathway, including TRAF3, TRAF4, TRAF5, TNFRSF1A, LTBR, TNFAIP1, and TNFAIP3 (35). Moreover, Sedighi et al. (2019) reported that TNF-α receptor expression in AD was negatively correlated with miR-29a levels. Therefore, miR-29a may be associated with AD by regulating the neuroinflammation levels (36).

MiR-34a, a miRNA regulated by NF-кB, was upregulated in the hippocampal CA1 region of AD patients. Bhattacharjee et al. (2016) found that miR-34a modulated TREM2 (a microglial receptor that triggers expression in myeloid cells), a crucial molecule of Aβ42 peptide clearance in AD. Downregulation of TREM2 levels was observed in the CA1 region in AD patients (37, 38). Rare variants R47H of TREM2 have been linked to an increased risk of AD, indicating that targeting miR-34a might be a therapeutic strategy for AD treatment (39).

MiR-126 regulated inflammation by targeting NF-κB pathway components and vascular cell adhesion molecule 1 (VCAM-1). The VCAM-1 mRNA was not expressed in quiescent endothelium cells, but pro-inflammatory cytokines could activate NF-κB and IRF-1, thereby inducing the transcription of VCAM-1. Overexpression of miR-126 could decrease VCAM-1 levels, suggesting miR-126 regulated VCAM-1 levels in quiescent cells (40). Moreover, elevated levels of miR-126 increased Aβ42-induced toxicity and interfered with the neuroprotective effects of IGF-1 by inhibiting PI3K and ERK pathways (41), suggesting miR-126 may be a potential molecular target for AD treatment.

MiR-146a was another NF-κB-dependent miRNA, that targeted transmembrane β-amyloid precursor protein (APP) associated TSPAN12, and inflammatory mediators interleukin receptor-associated kinase IRAK-1 (42). Therefore, miRNA-146a could be used as a potential diagnostic biomarker for AD and other age-related neurological disorders.

MiR-155 was also a known target for NF-кB pathway. Guedes et al. (2014) found that miR-155 was increased in the brains of AD animals. Moreover, the levels of miR-155 depended on the transcription factor c-Jun, which preceded extracellular Aβ accumulation and concomitant hyperactivation of microglia and astrocytes (43). Interestingly, Song and Lee (2015). found that miR-155 could regulate T lymphocyte function, suggesting that miR-155 was an immune-related miRNA associated with AD (44). Therefore, miR-155 may not only be a valuable candidate biomarker of AD, but also a therapeutic target for AD.

It has been reported that miR-132 improved cognitive function in AD rats by inhibiting the MAPK1 signaling pathway. Bioinformatics analysis revealed a target inhibitory relationship between miR-132 and MAPK1. It was found that upregulation of miR-132 reversed the negative effects of MAPK1 silencing in AD rats. Mechanistically, miR-132 inhibited the expression of iNOS and oxidative stress in the hippocampus by inhibiting the expression of MAPK1, and improved the cognitive function of AD rats, which was helpful for understanding the pathogenesis of AD and developing new clinical treatments (48).

Multiple studies have showed that some miRNAs, including miR-223, were dysregulated in AD and played important roles in AD pathogenesis (49, 50). MiR-7-5p, miR-22-3p, and miR-30-5p could bind to the NLRP3-mRNA, hindered protein translation, and prevented the formation of inflammasome protein complexes. In the brains of AD patients, other studies have also found downregulation of miR-7 and miR-30e as well as low levels of circulating miRNA-22 (51, 52). La Rosa et al. (2021) analyzed the expression of miRNAs in AD patients, and found that miR-223-3p and miR-7-5p levels were increased in AD patients, but failed to downregulate NLRP3 and proinflammatory cytokines (53). In particular, miR-223-3p bound to the highly conserved 3’UTR of NLRP3 and acted as a NLRP3 miRNA inhibitor (54, 55).

MiR-101 was downregulated in temporal and parietal regions of human AD cortex (56). Downregulation of miR-101 leaded to upregulation of COX2 in AD and induced inflammatory responses in the brain, thus significantly promoting AD pathology (57).

The miR-181 family was also involved in neuroinflammation and is associated with AD (58). Rodriguez-Ortiz et al. (2014) found that miR-181a was significantly upregulated in the hippocampus of 12-month-old AD mice. Enhancement of the expression of miR-181 in SH-SY5Y cells significantly reduced SIRT1 and c-Fos levels (59). Moreover, miR-181 family have been linked to the stress responses, in which miR181d was discovered to target multiple stress and metabolic related signaling pathway. Collectively, these results suggest a possible between the miR-181 family in stress response and neuroinflammation in AD (60).

Together, miRNAs could participate in the regulation of MAPK pathway, NF-κB signaling, NLRP3 inflammasome, and other inflammatory molecular pathways to regulate neuroinflammation. Among them, NF-κB signaling related miRNAs include miR-29 family, miR-34a, miR-126-3p, miR-146a and miR-155. These miRNAs may not only be valuable candidate biomarkers but also therapeutic targets for AD.

MiR-22 alleviated inflammation in IS by inhibiting the p38 MAPK/NF-κB pathway (62). Dong et al. (2019) found that downregulation of miR-22 upregulated inflammatory factors and overexpression of miR-22 decreased inflammatory factors expression in vitro, suggesting that targeting miR-22 might be beneficial for the prevention and treatment of IS.

MiR-155 participated in cell damage by regulating the expression of TLR4 and MyD88, which might be important for the diagnosis and treatment of IS. Moreover, the miR-155 expression level was found to be higher in the serum of IS patients, but it decreased after treatment (45). Chen et al. (2021) found that the knockout of miR-155 improved the neurological function of mice and inhibited TLR4 and MyD88 protein levels. Additionally, miR-155 inhibition enhanced the proliferation of SH-SY5Y cells, reduced apoptosis levels, and increased the expression of TLR4 and MyD88. Interestingly, treatment with TLR4/MyD88 pathway inhibitors completely reversed the effects of miR-155 (46), indicating that miR-155 could regulate disease by targeting the TLR4/MyD88 pathway in IS.

Yang et al. (2021) found that the decreased expression of miR-195 and increased NF-κB expression were occurred in oxygen–glucose deprivation (OGD)-treated HUVECs. Importantly, miR-195 overexpression inhibited apoptosis and promoted cell proliferation by regulating IKKα-mediated NF-κB signaling pathway, suggesting that miR-195 inhibited the IKKα-mediated NF-κB pathway to have a protective role, offering a novel possible strategy for the clinical treatment of IS (63). In addition, CD40, a protein expressed in nerve and blood vessel cells in the brain, could stimulate the NF-κB pathway, but its activity could be directly inhibited by miR-195. CD40 levels increased in the cerebral apoplexy hemisphere, and its level was associated with the post-ischemic inflammation. CD40 deficiency reduced cell adhesion, reduced NF-κB signaling pathway, and increased iNOS level. Intravenous injection of nanoparticle-carried miR-195 into rats at the acute stage of IS reduced the volume of the injured brain by up to 45% and improved functional recovery (64), suggesting that treatment with miR-195 was beneficial for treating acute IS, which might act as a new target of IS.

MiR-203 protected microglia-mediated brain injury by inhibiting NF-κB signaling pathway during ischemia. Z. Yang et al. (2015b) found that miR-203 directly bound to the 3’UTR of MyD88 to inhibit its expression, which suppressed neurological inflammatory response and improved neuronal functions (66). This finding suggests that miRNA-203 is a novel target that can attenuate inflammatory response in IS and reduce neuronal damage.

Overexpression of miR-1202 inhibited the activation of the TLR4/NF-κB inflammatory signaling pathway, thereby exerting a neuroprotective effect. Song et al. (2020) found that miR-1202 expression was downregulated and Rab1a expression was upregulated in OGD/R-induced human microglial cell line. Rab1a (NF-κB upstream signaling protein) could up-regulate the expression level of TLR4 in OGD/R-treated cells, and promoted the activation of NF-κB signaling pathway (67). Interestingly, miR-1202 directly targeted Rab1a to inhibit NF-κB signaling pathway, and reduced inflammatory response and apoptosis, exhibiting a protective effect.

Reportedly, miR-20b was involved in cerebral ischemia-induced inflammation by targeting NLRP3. Downregulation of miRNA-20b inhibited the NLRP3 signaling pathway and the downstream IL-1β and IL-18 levels, and reduced ATP and ROS levels, thereby mitigating inflammatory damage after IS (68).

MiR-181 was highly expressed in healthy human brains and was downregulated in acute ischemic stroke (AIS) patients. Ma et al. (2016) found that downregulated miR-181c-3p levels observed in OGD-treated cortical neurons and OGD-treated exosomes. CXCL1 and inflammatory cytokine expression in astrocytes were decreased by OGD-treated cortical neuronal exosomes. Moreover, the miR-181c-3p mimics against CXCL1 inhibited astrocytic inflammation levels by downregulating CXCL1 (61).

In addition, the expression of miR-195 was significantly downregulated in the plasma samples of AIS patients, with a significant negative correlation with Stroke Scale score. Consistently, miR-195 levels were also decreased in the plasma in MCAO mice, and intracerebral injection of miR-195 lentivirus inhibited inflammatory signal transduction. Mechanistically, the authors found that miR-195 could directly target both CX3CL1 and CX3CR1, and inhibited CX3CR1-mediated neuroinflammation (65).

In conclusion, miRNAs can directly or indirectly regulate several inflammatory pathways, such as NF-κB signaling pathway and NLRP3. Targeting the regulation of miRNA facilitates the diagnosis and treatment of IS.

It was reported that overexpression of miR-140-5p decreased TLR4 levels, and inhibited MyD88/TRIF/NF-κB inflammatory signaling pathway, thereby reduced brain injury and neuroinflammation after ICH (33), suggesting that targeting miR-140-5p is beneficial to therapeutic treatment of ICH.

Moreover, thrombin-induced downregulation of miR-181c promoted MLL1 levels, and increased the activity of NF-κB signaling (69). These results suggest that proinflammatory NF-κB activity stimulated by thrombin is involved in the pathology of ICH, which could be inhibited by overexpression of miR-181c. Therefore, miR-181c mimic therapy holds promise for regulating thrombin-driven microglial activation after ICH.

MiR-195 inhibited NF-κB signaling, including IKKα and p-IκB, which could affect the reduction of ubiquitin-dependent IκB degradation, leading to the inhibition of nuclear translocation of p65/p50 and RelB/p52, and downregulation downstream pro-inflammatory cytokine levels in the rat brain, suggesting that miR-195 has anti-inflammatory effects. Moreover, experimental results showed that miR-195 carried by nanoparticles and injected intravenously into rats at the acute stage of hemorrhagic stroke could reduce about 30% of the damaged brain volume (64). In conclusion, miR-195 could be used to treat ICH, since it directly blocks the NF-B pathway to exhibit its anti-inflammatory effects.

MiR-152 regulated the thioredoxin-interacting protein (TXNIP)-mediated NLRP3 activation, and inhibited neuroinflammation and neuronal death after ICH. Previous studies have shown that downregulated miR-152 was observed in ICH patients. Hu et al. (2020) found that miR-152 was downregulated in both collagenase-induced rat ICH model and hemin exposure model. Overexpression of miR-152 significantly alleviated hematoma, brain edema, and neurological deficits in rats with ICH. Mechanistically, overexpression of miR-152 blocked the interaction between TXNIP and NLRP3, and inhibited the activation of NLRP3 inflammasome (70), indicating that miR-152 played an active role in NLRP3 activation.

Wan et al. (2021) found that injecting miR-194-5p agomir into the brain tissue significantly inhibited NLRP3-mediated inflammation and alleviated the neuropathological damage in ICH rats. TRAF6 was further discovered to be one target of miR-194-5p. Overexpression of miR-194-5p reduced the interaction between NLRP3 and TRAF6, thereby reducing NLRP3 inflammasome-mediated neuroinflammation (71).

Moreover, miR-223 could directly bind to the 3’UTR of mRNA of NLRP3, and inhibit NLRP3 expression, thereby reducing neuronal inflammation and improving neuronal function. The pathology of ICH was characterized with inflammation, nerve damage, and increase of brain water content in mice, and miR-223 could reduce these changes by down-regulation of NLRP3 inflammasome (72).

Inhibition of miRNA-155 promoted the BMAL1 levels, which further activated the nuclear factor erythroid 2-related f actor 2 (Nrf2) to alleviate ICH-induced secondary brain injury (SBI). Gong et al. (2021) established a rat model of ICH using autologous blood injections and found that BMAL1 protein levels were decreased in the ICH group. Moreover, ICH-induced oxidative stress, inflammation, brain edema, BBB damage, neuronal cell death, and neurological dysfunction were alleviated by overexpressing of BMAL1 (47). Therefore, the upregulation of BMAL1 could activate the Nrf2 signaling pathway to attenuate SBI after ICH, and the miR-155/BMAL1 might be a promising therapeutic target.

Overexpression of miR-183-5p reduced HO-1 expression and thus alleviated early injury after ICH. Y. Wang et al. (2020) found that miRNA-183-5p levels were significantly reduced after ICH occurrence in mice. Injecting miRNA-183-5p agomir reduced oxidative stress and neuroinflammatory responses by inhibiting the expression of HO-1 mRNA in ICH mice (73).

Serum miR-21-5p levels were increased and were correlated with NIHSS scores. Inhibition of miR-21-5p could attenuate inflammatory damage, thereby alleviating neurological deficits after ICH via targeting with dual-specificity phosphatase 8 (DUSP8) (74).

It was reported that miR-132 enhanced cholinergic blockade of inflammatory responses and protected against ischemia-induced neuronal cell death by targeting acetylcholinesterase (AChE). Zhang et al. (2017) found that overexpression of miR-132 in the mice brain reduced neurological impairment and inflammatory damage. Consistently, the downregulation of miR-132 increased inflammation and apoptosis (76). In conclusion, the protective effect of miR-132 in ICH mouse models provides new opportunities for therapeutic interventions.

Wang et al. (2021) used collagenase-induced ICH mouse models and miR-144/451 knockout mice, and found that knockout of miR-144/451 increased TNF-α and IL-1β levels, and oxidative stress in ICH mice. Furthermore, the authors found that deletion of miR-144/451 suppressed the activity of the miR-451-14-3-3ζ-FoxO3 regulatory axis in ICH mice. Moreover, compared with miR-144, miR-451 was dominant in regulating ICH (98).

Overexpression of miR-590-5p significantly improved brain edema and neurological function and reduced neuroinflammation in ICH mice. Guo et al. (2018) showed that pelino-1 (Peli1) could be directly targeted by miR-590-5p. Overexpression of miR-590-5p significantly decreased Peli1 levels. Meanwhile, overexpression of Peli1 partially eliminated the inhibitory effect of miR-590-5p mimic (77).

In summary, multiple miRNAs have been demonstrated to hold therapeutic effects in ICH by targeting NF-κB signaling pathway, or directly binding to the 3’UTR of NLRP3 to inhibit its activation. Alternatively, miRNAs can activate Nrf2 signaling pathway to attenuate ICH-induced SBI.

Ge et al. (2016) found that miR-21-5p could regulate NF-κB signaling pathway to inhibit inflammation. In vitro experiments, miR-21-5p has been found to promote the activation of the angiopoietin 1 (Ang-1)/tyrosine kinase receptor 2 (Tie-2) pathway, thus promoting angiogenesis and repair of brain tissue. This study suggested that miR-21-5p not only inhibited inflammation by affecting the NF-κB signaling pathway, but was also closely related to apoptosis and vascular repair (75).

Li et al. (2020) showed that the upregulation of miR-23a inhibited neuroinflammation and improved long-term neural function. Overexpression of miR-23a inhibited caspase 3 activity and the release of inflammatory mediators, suggesting miR-23a could inhibit the apoptosis and inflammatory responses. Moreover, miR-23a could directly target the phosphatase and tensin homologue (PTEN). Overexpression of miR-23a activated the AKT/mTOR pathway in TBI mouse models, as evidenced by the increased levels of p-AKT and p-mTOR (78).

MiR-200b was reported to regulate the inflammatory response by modulating the MAPK pathway in microglia. The miRNA-200b levels were downregulated in activated microglia. Jadhav et al. (2014) found that the transcription factor c-Jun was the target of miR-200b, and inhibition of miR-200b in microglia enhanced JNK activity modulated microglial inflammatory process, and increasing neuronal apoptosis (79).

In summary, miR-200b targeted the cJun/MAPK signaling pathway and reduced the inflammatory response of activated microglia, indicating that miR-200b is a possible intervention target in chronic neuroinflammation. miRNA targeting neuroinflammation and its downstream effects, including NF-κB signaling pathway, MAPK signaling pathway and NLRP3 inflammasome, have important implications for improving the prognosis of TBI.