Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling

Jin, Lingting; Zhang, Jingjing; Hua, Xin; Xu, Xingxing; Li, Jia; Wang, Jiaojiao; Wang, Mianxian; Liu, Huitao; Qiu, Haoyu; Chen, Man; Zhang, Xu; Wang, Y; Huang, Zhihui

doi:10.1038/s41419-022-05202-z

Cited by 17 publications

(7 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sarm1 is highly expressed in neurons, however its expression has been noted in other tissues, including immune cells (Jin et al, 2022; Panneerselvam et al, 2013). To specifically delete Sarm1 in TH + neurons we crossed a Sarm1 conditional knockout allele to TH-Cre ( Th-Cre; Sarm1 fl/fl ) mice.…”

Section: Resultsmentioning

confidence: 99%

An axon – T cell feedback loop enhances inflammation and axon degeneration

Liu

Wang

Kutsovsky

et al. 2023

Preprint

View full text Add to dashboard Cite

Inflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the beta2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.

show abstract

Section: Resultsmentioning

confidence: 99%

An axon – T cell feedback loop enhances inflammation and axon degeneration

Liu

Wang

Kutsovsky

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…1 ). Our previous studies have shown that SARM1 expression is increased in acute spinal cord injury [ 46 ]. This may suggest that SARM1 plays different roles in different disease models.…”

Section: Discussionmentioning

confidence: 99%

SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease

Miao¹,

Qian²,

Du³

et al. 2024

Aging and disease

Self Cite

View full text Add to dashboard Cite

Neuroinflammation plays a crucial role in the pathogenesis and progression of Alzheimer's disease (AD). The Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) has been shown to promote axonal degeneration and is involved in neuroinflammation. However, the role of SARM1 in AD remains unclear. In this study, we found that SARM1 was reduced in hippocampal neurons of AD model mice. Interestingly, conditional knockout (CKO) of SARM1 in the central nervous system (CNS, SARM1 Nestin -CKO mice) delayed the cognitive decline in APP/PS1 AD model mice. Furthermore, SARM1 deletion reduced the Aβ deposition and inflammatory infiltration in the hippocampus and inhibited neurodegeneration in APP/PS1 AD model mice. Further investigation into the underlying mechanisms revealed that the signaling of tumor necrosis factor-α (TNF-α) was downregulated in the hippocampus tissues of APP/PS1;SARM1 Nestin -CKO mice, thereby alleviating the cognitive decline, Aβ deposition and inflammatory infiltration. These findings identify unrecognized functions of SARM1 in promoting AD and reveal the SARM1-TNF-α pathway in AD model mice.

show abstract

“…SARM1, unlike other members of the MyD88 family, is abundant in the murine nervous system, particularly in neurons ( Kim et al, 2007 ; Chen et al, 2011 ). SARM1 protein is not found in mouse microglia but is expressed in astrocytes and plays a role in neuroinflammation ( Lin et al, 2014 ; Liu et al, 2021 ; Jin et al, 2022 ). We have shown that SARM1 is present in mouse oligodendrocytes in vitro and in vivo and zebrafish oligodendrocytes express sarm1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…The authors postulate that the death is likely secondary to the role of Sarm1 in axons yet there remains the intriguing possibility that Sarm1 may, in addition, be required cell-autonomously in oligodendrocytes for some or all of the cell death in this model ( Ko et al, 2020 ). Interestingly, astrocytes do appear to upregulate expression of SARM1 in response to spinal cord injury and also to modulate neuroinflammation in experimental autoimmune encephalomyelitis ( Liu et al, 2021 ; Jin et al, 2022 ). Finally, Sarm1 KO mice demonstrate less myelin loss after traumatic brain injury, independent from protection against axon loss ( Marion et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice

Mutschler

Chen

Turmaine

et al. 2023

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.

show abstract

Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling

Cited by 17 publications

References 52 publications

An axon – T cell feedback loop enhances inflammation and axon degeneration

An axon – T cell feedback loop enhances inflammation and axon degeneration

SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease

SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice

Contact Info

Product

Resources

About