Menstrual blood-derived endometrial stem cells inhibit neuroinflammation by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 pathway

Neuroinflammation is a common response that accompanies various disorders including infectious and noninfectious neurological and psychiatric diseases such as sepsis-associated encephalopathy, intracerebral haemorrhage, Alzheimer’s disease (AD), Parkinson’s disease (PD), depression and schizophrenia (Brandao et al., 2020, Mishra et al., 2021). Early inflammatory reactions contribute to neuronal repair and maintain homeostasis in the nervous system. However, chronic and aberrant inflammation leads to neuronal death and brain atrophy, which results in mental and behavioural abnormalities (Moyse et al., 2022, Teleanu et al., 2022). The modulation of neuroinflammation has become a promising therapeutic strategy for neurological and psychiatric diseases, however, only a few effective methods are available to manipulate neuroinflammation in the clinic (Dash et al., 2021, Kwon and Koh, 2020, Mishra et al., 2021).

Microglia are resident immune cells and the first line of immune defence in the nervous system. Resting microglia monitor homeostasis in the brain. Once activated by pathogens, inflammatory factors or brain injury, microglia release cytokines and mediators to promote the clearance of the pathogens and repair of the nerve tissue (Mendes and Majewska, 2021, Uriarte Huarte et al., 2021). Microglia are the pioneering cells that initiate the inflammatory response in the brain and influence other cells including astrocytes and neurons, resulting in subsequent inflammatory reactions (Fujita and Yamashita, 2021, Madore et al., 2020). Under pathophysiological conditions, dysfunctional microglia continuously secrete proinflammatory factors, resulting in neuronal death and nerve injury (Lewcock et al., 2020, Wright-Jin and Gutmann, 2019). Recent studies of the transcriptome and by single cell sequencing revealed that microglia show regional and pathological heterogeneity, which may represent various functional groups of microglia (Masuda et al., 2020, Tan et al., 2020). These findings suggest that microglia interventions may be an efficient means for the treatment of neuroinflammation-associated diseases.

Mesenchymal stem cells (MSCs) secrete a variety of factors and have immunomodulatory effects (Chen et al., 2018, Song et al., 2020, Wang et al., 2014). Recent studies have shown a promising potential of MSCs for the treatment of inflammation-associated organ dysfunction (Joshi et al., 2021, Skok, 2021). MSCs alleviate pathological symptoms and protect the organs from injuries by paracrine signalling, organelle transmission, exosome transfer, implantation and differentiation. The mechanism of these effects may involve immunomodulation, antioxidant activity, anti-apoptotic activity, metabolism regulation of metabolism and autophagy (He et al., 2021, Seo et al., 2021). However, only a few studies have reported the effects of MSCs on the neuroinflammatory response in the brain and the results are controversial (Li et al., 2018, Liu et al., 2022, Qin et al., 2022). The mechanism of actions of MSCs in neuroinflammation is incompletely understood (Dabrowska et al., 2019, Do et al., 2021, Qin et al., 2021).

Our previous study has shown that MSCs regulate the functions of microglia in vitro (Xu et al., 2018). Recently, we have isolated a new type of MSCs from the female menstrual blood (MenSCs) that secrete a variety of the cytokines and mediators (Liu et al., 2018). This evidence suggested to examine the effects of MenSCs on neuroinflammation and microglia and to investigate possible mechanisms of action in the present study. We demonstrated that intravenous transplantation of MenSCs suppressed the inflammatory response in neuroinflammation model of animals and cells while promoting the inflammatory response in naïve animals and cells. We also provided evidence demonstrating a potential role of microglia and the Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (Casp1) signalling pathway in neuroinflammation. These findings may be very helpful for the development of an alternative MSC-based therapy for neuroinflammation-associated disorders.

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