Roles of Siglecs in neurodegenerative diseases

Siew, Jian Jing; Chern, Yijuang; Khoo, Kay‐Hooi; Angata, Takashi

doi:10.1016/j.mam.2022.101141

Cited by 14 publications

(6 citation statements)

References 179 publications

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“…Thus, human microglia demonstrate the expression of various SIGLEC receptors. In line, expression of Siglec-3/CD33 and Siglec-E to -H, next to evolutionary conserved SIGLECs, has been described in mouse microglia ( 64 – 69 ).…”

Section: Main Textmentioning

confidence: 76%

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Wißfeld,

Abou Assale,

Cuevas-Rios

et al. 2024

Front. Neurol.

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Sialic acids, commonly found as the terminal carbohydrate on the glycocalyx of mammalian cells, are pivotal checkpoint inhibitors of the innate immune system, particularly within the central nervous system (CNS). Sialic acid-binding immunoglobulin-like lectins (SIGLECs) expressed on microglia are key players in maintaining microglial homeostasis by recognizing intact sialylation. The finely balanced sialic acid-SIGLEC system ensures the prevention of excessive and detrimental immune responses in the CNS. However, loss of sialylation and SIGLEC receptor dysfunctions contribute to several chronic CNS diseases. Genetic variants of SIGLEC3/CD33, SIGLEC11, and SIGLEC14 have been associated with neurodegenerative diseases such as Alzheimer’s disease, while sialyltransferase ST8SIA2 and SIGLEC4/MAG have been linked to psychiatric diseases such as schizophrenia, bipolar disorders, and autism spectrum disorders. Consequently, immune-modulatory functions of polysialic acids and SIGLEC binding antibodies have been exploited experimentally in animal models of Alzheimer’s disease and inflammation-induced CNS tissue damage, including retinal damage. While the potential of these therapeutic approaches is evident, only a few therapies to target either sialylation or SIGLEC receptors have been tested in patient clinical trials. Here, we provide an overview of the critical role played by the sialic acid-SIGLEC axis in shaping microglial activation and function within the context of neurodegeneration and synaptopathies and discuss the current landscape of therapies that target sialylation or SIGLECs.

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Section: Main Textmentioning

confidence: 76%

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Wißfeld,

Abou Assale,

Cuevas-Rios

et al. 2024

Front. Neurol.

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“…Many studies have focused on mitigating secondary complications in SCI, such as neuroinflammation and neuronal apoptosis, to improve functional recovery 53,54 . Neuroinflammation is a response to CNS injury 55 characterized by a strong inflammatory response mediated by activated microglia 56 . Microglia act as the defense cells of the CNS, helping to maintain its homeostasis 57 .…”

Section: Discussionmentioning

confidence: 99%

“…53,54 Neuroinflammation is a response to CNS injury 55 characterized by a strong inflammatory response mediated by activated microglia. 56 Microglia act as the defense cells of the CNS, helping to maintain its homeostasis. 57 However, microglia overactivation can result in the release of a variety of pro-inflammatory mediators, which are thought to be markers and drivers of neuroinflammation-related diseases.…”

Section: Alpinetin Improved Axonal Regeneration After Scimentioning

confidence: 99%

Alpinetin inhibits neuroinflammation and neuronal apoptosis via targeting the JAK2/STAT3 signaling pathway in spinal cord injury

et al. 2023

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Background A growing body of research shows that drug monomers from traditional Chinese herbal medicines have antineuroinflammatory and neuroprotective effects that can significantly improve the recovery of motor function after spinal cord injury (SCI). Here, we explore the role and molecular mechanisms of Alpinetin on activating microglia‐mediated neuroinflammation and neuronal apoptosis after SCI. Methods Stimulation of microglia with lipopolysaccharide (LPS) to simulate neuroinflammation models in vitro, the effect of Alpinetin on the release of pro‐inflammatory mediators in LPS‐induced microglia and its mechanism were detected. In addition, a co‐culture system of microglia and neuronal cells was constructed to assess the effect of Alpinetin on activating microglia‐mediated neuronal apoptosis. Finally, rat spinal cord injury models were used to study the effects on inflammation, neuronal apoptosis, axonal regeneration, and motor function recovery in Alpinetin. Results Alpinetin inhibits microglia‐mediated neuroinflammation and activity of the JAK2/STAT3 pathway. Alpinetin can also reverse activated microglia‐mediated reactive oxygen species (ROS) production and decrease of mitochondrial membrane potential (MMP) in PC12 neuronal cells. In addition, in vivo Alpinetin significantly inhibits the inflammatory response and neuronal apoptosis, improves axonal regeneration, and recovery of motor function. Conclusion Alpinetin can be used to treat neurodegenerative diseases and is a novel drug candidate for the treatment of microglia‐mediated neuroinflammation.

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“…Siglec-E, Siglec-F and Siglec-G, which resemble potential functional paralogs of human Siglec-9, Siglec-8 and Siglec-10, respectively (18). To this end, Siglec expression of tumor infiltrating and spleen-derived MDSCs in tumor-bearing and naïve mice was analyzed by assessing CD11b + Ly6G + and CD11b + Ly6C + populations which in the tumor context are described as gMDSCs and mMDSCs, retrospectively (17) (Supp.1 F).…”

Section: Cd33-related Inhibitory Siglec Receptors On Tumor-bearing An...mentioning

confidence: 94%

Engagement of sialylated glycans with Siglec receptors on myeloid suppressor cells inhibit anti-cancer immunity via CCL2

Wieboldt,

Carlini,

Lin

et al. 2023

Preprint

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Overexpression of sialic acids on glycans, called hypersialylation is a common alteration found in cancer. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on myeloid-derived suppressor cells (MDSCs) and their interaction with Siglec receptors. We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to strong reduction of their suppressive potential. We further identified CCL2 as mediator involved in T cell suppression upon interaction of sialoglycans and Siglec receptors on MDSCs. Our results provide mechanistic insights how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression.

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Roles of Siglecs in neurodegenerative diseases

Cited by 14 publications

References 179 publications

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Alpinetin inhibits neuroinflammation and neuronal apoptosis via targeting the JAK2/STAT3 signaling pathway in spinal cord injury

Engagement of sialylated glycans with Siglec receptors on myeloid suppressor cells inhibit anti-cancer immunity via CCL2

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