https://orcid.org/0009-0002-1688-0770
Abstract
Sterile alpha and toll interleukin receptor motif-containing protein 1 (SARM1) are primarily expressed in the mammalian nervous system, with their presence in neurons being associated with mitochondrial aggregation. SARM1 functions as a mediator of cell death and morphological changes, while also regulating Waller degeneration in nerve fibers and influencing glial cell formation.
Recent reports demonstrate SARM1 serves as a connector in the Toll-like receptor (TLR) pathway and plays a role in regulating inflammation during periods of stress such as infection, trauma, and hypoxia. These findings offer new insights into pathogenesis research and the prevention and treatment of neurodegenerative diseases and pathogen infections.
This review synthesizes recent findings on the immune-related mechanisms of SARM1, emphasizing its roles in inflammation and its functional impact on the nervous system and other bodily systems.
Understanding the multifaceted roles of SARM1 in immune regulation and neuronal health provides novel insights into its involvement in disease pathogenesis. These insights hold promise for advancing research into the prevention and treatment of neurodegenerative diseases and pathogen-induced conditions.
Introduction
Toll-like receptors (TLRs) are crucial pattern recognition receptors (PRRs) that induce innate and adaptive immunity by utilizing the C-terminal Toll/interleukin-1 receptor (TIR) protein–protein interaction domain to connect downstream adaptor molecules.1 The TIR domain of the receptor directly interacts with the adaptor TIR domain, thereby transmitting the downstream signal of TLRs.2 Currently, four canonical TIR domain-containing adaptors have been identified: myeloid differentiation factor 88 (MyD88), TIR domain-containing adaptor protein (TIRAP, also known as MAL), TIR domain-containing adaptor protein-inducible interferon (TRIF, also known as TICAM1) and TRIF-related adaptor molecule (TRAM, also known as TICAM2). They broadly serve as signaling or sorting adaptors for the TLR family, while non-canonical adaptors are recruited for more specific functions. Sterile alpha and TIR motif-containing 1 (SARM1) is a non-canonical adaptor that functions as a negative regulator of TLR signaling, blocking both TRIF- and MyD88-dependent pathways as well as the activation of transcription factors.3,4 In fact, SARM1 can also activate TLR signaling under specific conditions and participate in other pattern recognition receptors pathways,5 which will be discussed in the following sections. Based on this evidence, it is clear that SARM1 is unique and important among all known TLRS and adaptor proteins containing TIR domains.
The C-terminal TIR structure of SARM1 is the structural basis for its role in inflammation regulation. Reports since 2006 have shown that SARM1 negatively regulates TRIF and MyD88-dependent TLR signaling3 not only in mammals,4 but also widely in lower organisms.6–8 In contrast, SARM1 interferes with the immune response, akin to the mechanism employed by bacterial pathogens.9 Additionally, SARM1 specifically affects TRIF-dependent transcription factor activation and gene induction, leading to reduced expression of inflammatory factors. However, it does not impact TLR signaling mediated by MyD88 or non-TLR signaling mediated by TNF or RIG-I.10,11 Additionally, SARM1 is closely linked to neurodegeneration12 and mitochondrial damage.13,14
In normal physiological conditions, SARM1 exists as an octameric ring protein,15 with its ARM domain interacting with the TIR domain to inhibit NAD+ hydrolysis activity.16 Under stress, the NADase-active TIR domain is released, leading to substantial NAD+ degradation and subsequent energy depletion in axonal cells, which results in axonal degradation.15,17–19 Structurally, the SARM protein also contains the ARM repeat sequence and the SAM motif, which mediate protein–protein interactions to regulate the cytoskeleton and conduct intracellular signals.
SARM1 exhibits differential expression levels, localization, and multi-functionality across various tissues. SARM1 is primarily expressed in the brain, with widespread distribution in different brain regions, including the cerebral cortex, hippocampus, amygdala, cerebellum, and midbrain. However, SARM1 displays varying expression levels in different types of neurons and differentially expressed in glial cells under specific physiological or pathological conditions. Normally, neurons express a substantial amount of SARM1, with pyramidal cells in the hippocampus and Purkinje cells in the cerebellum showing the highest abundance,20 while several studies have reported that low expression of SARM1 in glial cells—supportive cells involved in nervous system regeneration.11,20 Interestingly, recent findings have highlighted significant SARM1 expression in astrocytes exposed to high doses of fructose21 and in pathological mouse spinal cord astrocytes,22 confirming the differential expression of SARM1 in the same cell type under distinct physiological states. During the embryonic development of mouse, the expression of SARM1 gradually increased in the brain, reaching its peak on day 18. This specific timeframe corresponds to a period characterized by extensive neuronal proliferation and programmed cell death. Besides, SARM1 is also considerably expressed in peripheral blood, primarily within lymphocytes, while exhibiting minimal expression in mononuclear macrophages and polymorphonuclear leukocytes.20
Several in vitro experiments on cells20,23,24 have reported that endogenous SARM1 is primarily co-localized with mitochondria, with a smaller fraction sparing in the cytoplasm. The mitochondrial localization accounts for approximately 70% of the total SARM1, while the remaining 30% is found in the cytoplasm.24 The translocation of SARM1 to mitochondria may be influenced by post-translational modification of its proteins.25 Notably, one study proposed that the SARM1 protein which located in mitochondria has a slightly higher molecular weight,25 and its n-terminal 27 amino acids (S27) possess hydrophobic and polybasic characteristics. This sequence acts as a mitochondrial targeting signal, facilitating the binding of SARM1 to mitochondria. Additionally, the aggregation of SARM1 protein within the mitochondria is facilitated by either or both the SAM domain and the TIR domain located at the C-terminus.13,20,26 This aggregation ultimately leads to cell damage through the mitochondrial pathway. These findings suggest a close association between SARM1 and cell damage, with the damage being dependent on mitochondria.26Based on the aforementioned experiments, the localization of SARM1 in different cellular environments influences its functionality. Specifically, the endoplasmic reticulum cleaves or connects 27 amino acid residues at the N-terminal of SARM1 to regulate protein delivery targeting the mitochondrial outer membrane. Consequently, depending on its localization, SARM1 can either initiate degeneration or cell death, or play a crucial role in regulating inflammatory factors.
As an adaptor protein for TLR receptors, SARM1 plays a crucial role in regulating immune-related inflammatory pathways. In this review, we talked about the direct and indirect effects of SARM1 on inflammatory factors within the NF-kB pathway, the NLRP3 inflammasome, and the MAPK pathway. Additionally, we summarized the role of SARM1 in the pathological changes observed in various organs and its involvement in pathogen infections. In this review, we put emphasis on the relationship between SARM1 and immunoinflammatory factors, intentionally excluding the Wallerian degeneration pathway, which has been covered in other reviews.27–29 Nonetheless, there are molecular similarities between SARM1-regulated inflammatory changes and Wallerian degeneration, suggesting that the processes discussed here might also play an as-yet-underappreciated role in axonal degeneration.30–32
SARM1 interacts with inflammatory factors
SARM1 regulates the NF-κB signaling pathway
Nuclear transcription factor kappaB (NF-κB) is an important transcriptional regulatory factor in cells. At rest, NF-κB protein binds to inhibitor IkB to form trimer complex p50-p65-IkB, which is inactivated in the cytoplasma. In response to stress, NF-κB and IκB protein dissociation exposes nuclear localization sequences (NLS), which are rapidly translocated into the nucleus and bind to their associated DNA motifs to induce target gene transcription. By regulating the expression of many genes, NF-κB is involved in many biological processes such as immune response, inflammatory response, apoptosis, and tumorigenesis.
Earlier studies suggested that SARM1, unlike the other four proteins with TIR domains, could not induce NF-κB-related signaling transcription.33 However, it was soon pointed out that SARM1 has a negative immune regulation effect and can inhibit inflammatory response. In recent years, more and more studies have proved that SARM1 can not only negatively regulate NF-κB signaling pathway, but also positively regulate it, leading to increased inflammation. SARM1 negatively regulates NF-κB signaling not directly, but indirectly by regulating other TLR receptors. SARM1 can inhibit the induction of TLR3 and TLR4-dependent genes, and can also directly target and block completely TRIF dependent NF-κB signaling pathways.4 The enhanced expression of SARM1 protein induced by injection of Poly (I: C) and LPS34 in cells can enhance the interaction between SARM1 and TRIF and inhibit the NF-κB signaling pathway, and the inhibition is positively correlated with the expression of SARM1 protein. This suggests that SARM1 inhibits TRIF-dependent NF-κB activation in a dose-dependent manner and is not regulated by SARM1 mRNA, but by the ligand-induced SARM1 protein (Fig. 1 left).
SARM1 interacts with inflammatory signaling pathways. (Left) SARM1 regulates the NF-κB signaling. (Right) SARM1 regulates NLRP3 pathway.
Characterization of TLR-induced cytokine responses in SARM1-deficient mouse macrophages showed that SARM1 is critical for NF-κB recruitment and RNA polymerase II of its regulatory CCL5 promoter.35 The requirement of SARM1 for CCL5 induction is not limited to the TLR pathway, as it is also evident in cytoplasmic RNA and DNA responses. However, activation of the CCL5 promoter is NF-κB-dependent. The expressions of IκB and NF-κB were up-regulated in bone marrow derived macrophages of SARM1−/−. All these suggest that the NF-κB regulation of SARM1 is not limited to TRIF.
Glial cell-derived neurotrophic factor (GDNF) is a member of the transforming growth factor β superfamily,36 which mediates the growth, differentiation, and migration of neurons and is required for the formation of axons and dendrites.37 In mice with autoimmune encephalomyelitis that conditionally knocked out SARM1 in astrocytes, SARM1-CKO caused an increase in the expression of GDNF in astrocytes, which inhibited NF-κB, thereby reducing the inflammatory response.
In mice with spinal cord injury that conditionally knocked out SARM1 in neurons and astrocytes,12 SARM1-CKO upregulated heat shock protein 70 (HSP70) to inhibit NF-κB signaling and reduce neuroinflammation. Among them, the inhibitory effect of HSP70 on NF-κB was also obtained in canine macrophages.38
SARM1 negatively regulates NLRP3 inflammasome activation
NLRP3 belongs to the sensing protein of inflammatory complex, which can detect pathogenic microorganisms and sterile stressors in the body, and plays a crucial role in innate immunity. NLRP3, a sensor-molecule activated by the classical activation pathway, binds to apoptosis-associated speckle like protein (ASC) through the N-terminal thermal protein domain to recruit Caspase-1, thus activating the NLRP3 inflammatory complex.
Activated Caspase-1 processes and modifiers the precursors of highly pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, promoting their maturation and secretion, and its powerful pro-inflammatory effect can directly affect the innate immune regulation process of the body against infection and injury.39 In addition to inflammation, Caspase-1 is also apoptotic, and its protein mediates Gasdermin-D (GSDMD) -dependent pyroptosis.40 In addition, NLRP3 also has a non-classical activation pathway, which is triggered by lipopolysaccharide (LPS) of Gram-negative bacteria. The LPS entering the body effectively activates Caspase-4/5 and Caspase-11, and the activated protein cuts GSDMD to free its N-terminal. The free N-terminal induces pyroptosis and activates NLRP3 inflammasome activity.41 NLRP3 inflammasome-mediated inflammatory cytokines play a dual role in the regulation of human diseases: on the one hand, they are harmful in the pathogenesis of inflammatory and metabolic diseases, and on the other hand, they play a beneficial role in many infectious diseases and some cancers.42
In order to maintain a stable intracellular environment, it is necessary to regulate the balance between inflammatory response and cell survival. SARM1, as an immunomodulatory molecule, plays an important role in balancing the relationship between NLRP3-dependent IL-1β release and cell apoptosis. SARM1 inhibits ASC oligomerization through its TIR domain interaction with the NLRP3 inflammasome, resulting in the inability of ASC to form ASC spots, and the inability of PRR and pro-caspase-1 to connect to generate Caspase-1, thus inhibiting the maturation and release of IL-1β.5 In LPS-activated SARM1−/− macrophages, the activation of inflammasome causes the release of a large number of inflammatory factors and the shear activation of GSDMD, but the resulting pyroptosis is significantly reduced, that is, the phenomenon of “over-activation” between the release of inflammatory factors and the separation of cell cleavage occurs.43 Consistent with this, IL-1β release decreased and pyroptosis increased after increasing SARM1 expression, which may be related to SARM1 clustering in mitochondria after inflammasome activation. SARM1 locates in mitochondria and induces mitochondrial depolarization, thereby promoting pyroptosis. In another study of the mechanism of activation of the NLRP3 inflammasome, it was written that in environments rich in hazardous associated molecular patterns (DAMP), DAMP-induced mitochondrial depolarization in macrophages eliminates Caspase-1 processing, and IL-1β secretion is similarly reduced. However, neutrophils cultured in DAMP rich environments did not observe this depolarization due to lack of SARM1 expression, nor did they affect IL-1β secretion.44 This suggests that SARM1 acts upstream of the Caspase-1 processing step and regulates NLRP3 activation through the mitochondrial pathway.
In addition, SARM1 inhibits LPS-induced sepsis, further confirming that SARM1 inhibits the release of cellular inflammatory factors induced by non-classical NLRP3 activation and promotes Caspase-11-mediated pyroptosis.5
It can be concluded from the above studies that SARM1 inhibits both classical and non-classical NLRP3 inflammasome activation and plays a key role in regulating NLRP3-dependent Caspase-1 production and the occurrence of pyroptosis (Fig. 1 right).
SARM1 negatively interacts with the MAPK cascade
Mitogen-activated protein kinase (MAPK) signaling pathway is an important signal transduction system widely existing in the body, and is involved in mediating various physiological and pathological processes such as cell growth, development, differentiation and apoptosis.45 The MAPK family consists of three main signaling pathways: extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase.
The MAPK pathway, which is mainly composed of three MAPKKKs (MEKK4/MLK2/DLK), two MAPKKs (MKK4/MKK7), three MAPKs (JNK1/JNK2/JNK3) and skeleton protein JIP3, activates and regulates axon disease and inflammation.46 SARM1 is necessary for the function of this MAPK cascade pathway, and shows a complex regulation that can directly regulate MAPK molecules and negatively regulate TRIF, thereby affecting its downstream MAPK molecules.3 SARM1 acts on the MAPKKK family and the downstream MAPKK family,46 and then polymerizes to the JNKs of the MAPK family. JNKs promote the release of cytochrome c in mitochondria into the cytoplasm, resulting in the activation of Caspase enzyme, leading to inflammation and axonal degeneration. Another point of interest in this study is that MKK4 and its downstream JNK1 and JNK2 are important molecules in regulating damaged axonal degeneration in the SARM-MAPK reaction associated with axonal degeneration. MAPK waterfall reaction causes local axon energy deficiency, which leads to calpain activation and morphological degradation.46 In the immune-related SARM1-JNK-c-Jun pathway, JNK2 and JNK3 play a central role in promoting the increased expression of Ccl2, Ccl7 and Ccl12 chemokines and the increased secretion of inflammatory factors such as IL-1β.47 It is suggested that SARM1 may play a pivotal role in axonal degeneration and neuroinflammation and is necessary to exert its effects.
In C. elegans, SARM1/TIR-1 plays a role in the inhibition of axonal degeneration. The upstream molecule of this inhibition is CaMKII/UNC-43, which is activated by high cytoplasmic calcium ion level and then directly interacts with TIR-1 to release self-inhibition of TIR domain. Activated TIR-1 recruits and activates NSY-1 MAPKKK, which is combined to form the UNC-43/TIR-1/NSY-1 complex. Further studies showed that the effector molecules of this axon inhibition pathway were p38 MAPK, PMK-3, and its downstream CEBP-1. Among them, the localization and activation of CaMKII is dependent on mitochondria, and its downstream SARM1 is activated only in the absence of axon mitochondria to play an axon protective role.
The above studies have shown that SARM1 polymerization can activate MAPK signaling pathway to cause axonal degeneration or play a role in axon protection, indicating that SARM1 is located upstream of MAPK pathway.26,48 However, a recent study has shown that the MAPK signaling pathway can accelerate the conversion of the survival factor NMNAT2, thereby indirectly activating SARM1. This means that the MAPK signaling pathway is not only located downstream of SARM1,49 that is, there is no strict signal transduction relationship between SARM1 and MAPK upstream or downstream. SARM1 can directly stimulate MAPK, and MAPK can also act on NMNAT2 to activate SARM.50 While the mechanisms leading to these conflicting conclusions have not yet been clarified, it could mean that there are feedback mechanisms that reinforce the response between SARM1 and MAPK signals.
The role of SARM1 in various systems
SARM1 and neurodegenerative diseases
SARM1 not only has the ability to change axonal degeneration, but also affects the innate immune response.51 Inducing cytokine expression is a key step in inducing innate immunity after TLR activation.
In the multiple sclerosis mouse model established by inducing experimental autoimmune encephalomyelitis (EAE),22 SARM1 expression was significantly up-regulated in the cerebellum, neck, thoracic and lumbar spinal cords of EAE mice. Double immunofluorescence staining of SARM1 and glial markers showed that SARM1 mainly existed in astrocytes, but no obvious staining was found in microglia. After conditionally knocking out the SARM1 gene in CKO astrocytes, SARM1-CKO mice were obtained. After EAE induction with MOG35-55 and pertussis toxin, it was found that in SARM1-CKO EAE mice, the proliferation of astrocytes was reduced, and microglia were converted from M1 (pro-inflammatory) to M2 (anti-inflammatory), further reducing the inflammatory response of EAE. It was also mentioned in the paper that SARM1-CKO has a protective effect on nerves, which can reduce inflammatory infiltration, inhibit the inhibition of axon demyelination and the reduction of neuronal death, and alleviate the disease of EAE (the onset becomes late).
In spinal cord injury (SCI) models, after conditionally knocking out SARM1 gene in neurons and astrocytes, NF-κB signaling is inhibited, reducing early neuroinflammation in SCI.12 The spinal cord of SARM1-CKO mice developed normally and their motor function was no different from that of SARMf/f control mice. Different from the significantly increased neuroinflammation in the whole process of mice in the control group after SCI, SARM1-CKO group significantly reduced the area of the injured site, inflammatory cell infiltration, and hematoma area at the injured site after SCI on the 3rd day after SCI. The number of inflammatory cells such as microglia, CD45 positive immune cells and astrocytes also decreased significantly. In general, conditional knockout of SARM1 can effectively reduce neuroinflammation in the early stage of SCI and may promote subsequent nerve regeneration.
In the model of repetitive mild closed cranial injury (rmCHI), rmCHI can cause white matter damage in the corpus callosum, cingulate tract, dentate gyrus of hippocampus and corymnus fornix. The mice were divided into four groups: wild type sham operation group, wild type rmCHI group, SARM1−/− sham operation group and SARM1−/-rmCHI group. Among them, there was no statistical difference in physiological and biochemical tests and behavioral tests between the two groups of mice undergoing sham surgery, suggesting that SARM1 knockout mice had no significant difference from wild-type mice at baseline level. In the two groups of mice treated with rmCHI, compared with wild-type mice, SARM1−/− mice showed less axonal damage and less activation of astrocytes and microglia, thus alleviating the inflammatory response of brain white matter caused by head injury. Not only that, the experiment also tested the motor and cognitive ability of mice, and conducted conditioned fear experiment. The test results of the three experiments all showed that SARM1 loss had a protective effect on neurons, and showed improvement in motor, cognitive and conditioned response.52
In the sciatic nerve injury model, the up-regulation of chemokine expression in the dorsal root ganglion of SARM1−/− mice was strongly inhibited, effectively preventing the recruitment of macrophages to the damaged nerve site,47 and alleviating the local inflammatory injury. The authors hypothesize that neurons can detect distal axon damage and rapidly produce specific inflammatory and chemokines. This neuronal immune response is spatially and temporally isolated from injury-induced axonal degeneration. In cultured neurons, the expression level of chemokines increased rapidly even when the downstream signal of SARM1 was activated by dimerizing TIR domain without cutting off neurons, indicating that neuroimmunity induced by SARM1 was not related to axonal damage. In vivo experiments have shown that SARM1 cells autonomously regulate neuronal immune responses.
The function of SARM1 protein and its association with inflammation.
| Phenotype | The association of SARM1 with inflammation | Reference |
|---|---|---|
| Nervous system | ||
| Spinal cord injury (SCI) | The selective removal of SARM1 in neurons and astrocytes enhanced the recovery of behavioral performance following SCI. This effect was attributed to the promotion of neuronal regeneration during the intermediate phase of SCI and a decrease in neuroinflammation during the early phase, achieved by downregulating NF-κB signaling and potentially upregulating HSP70. | 12 |
| Experimental autoimmune encephalomyelitis(EAE) | The SARM1 in astrocytes inhibits the expression of GDNF, leading to neuronal inflammation and demyelination. Upregulation of GDNF in astrocytes suppresses the NF-κB signaling pathway. | 22 |
| Repeated mild closed head injury (rmCHI) | Activation of astroglia and microglia decreased in white matter damage, indicating a reduction in inflammation. | 52 |
| Traumatic injury model | The SARM1-MAPK pathway disrupts the energy balance in axons, leading to ATP depletion before the physical breakdown of the damaged axon. This depletion subsequently triggers calpain activation and results in morphological degradation. Besides, SARM1 knockout significantly reduces the upregulation of Ccl7 and Ccl12 in damaged neurons through the JNK-c-Jun pathway. | 46,47 |
| Nmnat2V98M/R232Q Mutation model | NMNAT2 acts as an inhibitor of SARM1, and studies on NMNAT2 mutant mice have demonstrated a decrease in programmed axonal degeneration. This reduction includes improvements in progressive motor function, reduced peripheral axon loss, and decreased macrophage infiltration, all of which are entirely dependent on the presence of SARM1. | (Dingwall et al. 2022)69 |
| Skin | ||
| Plantar incision | Celastrol pretreatment up-regulates SARM1 expression and inhibits NF-κB signaling pathway activation, which in turn reduces pro-inflammatory cytokines release and pain-related behaviors | 54 |
| Liver | ||
| High fat diet model | SARM1-deletion was found to alleviate the inflammatory response caused by HFD. This was achieved through the inactivation of TLR4/7/9 and NF-κB pathways. Additionally, the deletion of SARM1 led to a reduction in the expressions of inflammation-associated molecules in the hypothalamus of HFD-fed mice. | 21 |
| Liver fibrosis model | In the context of hepatic stellate cells (HSCs), TRPV1 is capable of impeding pro-inflammatory activation by binding to the TIR domain of SARM1. This interaction effectively inhibits NF-κB activation and the subsequent production of pro-inflammatory cytokines. | 2 |
| Pathogen infection | ||
| Klebsiella pneumoniae infection | SARM1 is essential for Klebsiella-induced interleukin-10 (IL-10) production by modulating the p38-type I interferon (IFN) axis, which inhibits the activation of the Klebsiella-induced absent in melanoma 2 (AIM2) inflammasome, thereby reducing IL-1β production and limiting subsequent inflammation. | 55 |
| Mycobacteroides abscessus infection | As a negative regulator of TLR signaling, the low levels of SARM1 plays a role in the upregulated inflammatory responses in patients. | 56 |
| Respiratory syncytial virus(RSV) infection | SARM1 suppression resulted in an uncontrolled immune response to RSV, characterized by increased TRIF expression. High TRIF expression led to a pronounced Th1 response and elevated levels of IFN-γ, which subsequently exacerbated airway inflammation and airway hyperresponsiveness (AHR). | (Long et al. 2015)70, (Liu et al. 2014)57 |
| La Crosse virus (LACV) infection | LACV infection induced SARM1upregulation, which mediated cell death associated with oxidative stress response and mitochondrial damage. | 58 |
| West Nile virus(MNV) infection | Loss of SARM1 linked to increased viral replication, reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. | 59,60 |
| Phenotype | The association of SARM1 with inflammation | Reference |
|---|---|---|
| Nervous system | ||
| Spinal cord injury (SCI) | The selective removal of SARM1 in neurons and astrocytes enhanced the recovery of behavioral performance following SCI. This effect was attributed to the promotion of neuronal regeneration during the intermediate phase of SCI and a decrease in neuroinflammation during the early phase, achieved by downregulating NF-κB signaling and potentially upregulating HSP70. | 12 |
| Experimental autoimmune encephalomyelitis(EAE) | The SARM1 in astrocytes inhibits the expression of GDNF, leading to neuronal inflammation and demyelination. Upregulation of GDNF in astrocytes suppresses the NF-κB signaling pathway. | 22 |
| Repeated mild closed head injury (rmCHI) | Activation of astroglia and microglia decreased in white matter damage, indicating a reduction in inflammation. | 52 |
| Traumatic injury model | The SARM1-MAPK pathway disrupts the energy balance in axons, leading to ATP depletion before the physical breakdown of the damaged axon. This depletion subsequently triggers calpain activation and results in morphological degradation. Besides, SARM1 knockout significantly reduces the upregulation of Ccl7 and Ccl12 in damaged neurons through the JNK-c-Jun pathway. | 46,47 |
| Nmnat2V98M/R232Q Mutation model | NMNAT2 acts as an inhibitor of SARM1, and studies on NMNAT2 mutant mice have demonstrated a decrease in programmed axonal degeneration. This reduction includes improvements in progressive motor function, reduced peripheral axon loss, and decreased macrophage infiltration, all of which are entirely dependent on the presence of SARM1. | (Dingwall et al. 2022)69 |
| Skin | ||
| Plantar incision | Celastrol pretreatment up-regulates SARM1 expression and inhibits NF-κB signaling pathway activation, which in turn reduces pro-inflammatory cytokines release and pain-related behaviors | 54 |
| Liver | ||
| High fat diet model | SARM1-deletion was found to alleviate the inflammatory response caused by HFD. This was achieved through the inactivation of TLR4/7/9 and NF-κB pathways. Additionally, the deletion of SARM1 led to a reduction in the expressions of inflammation-associated molecules in the hypothalamus of HFD-fed mice. | 21 |
| Liver fibrosis model | In the context of hepatic stellate cells (HSCs), TRPV1 is capable of impeding pro-inflammatory activation by binding to the TIR domain of SARM1. This interaction effectively inhibits NF-κB activation and the subsequent production of pro-inflammatory cytokines. | 2 |
| Pathogen infection | ||
| Klebsiella pneumoniae infection | SARM1 is essential for Klebsiella-induced interleukin-10 (IL-10) production by modulating the p38-type I interferon (IFN) axis, which inhibits the activation of the Klebsiella-induced absent in melanoma 2 (AIM2) inflammasome, thereby reducing IL-1β production and limiting subsequent inflammation. | 55 |
| Mycobacteroides abscessus infection | As a negative regulator of TLR signaling, the low levels of SARM1 plays a role in the upregulated inflammatory responses in patients. | 56 |
| Respiratory syncytial virus(RSV) infection | SARM1 suppression resulted in an uncontrolled immune response to RSV, characterized by increased TRIF expression. High TRIF expression led to a pronounced Th1 response and elevated levels of IFN-γ, which subsequently exacerbated airway inflammation and airway hyperresponsiveness (AHR). | (Long et al. 2015)70, (Liu et al. 2014)57 |
| La Crosse virus (LACV) infection | LACV infection induced SARM1upregulation, which mediated cell death associated with oxidative stress response and mitochondrial damage. | 58 |
| West Nile virus(MNV) infection | Loss of SARM1 linked to increased viral replication, reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. | 59,60 |
The function of SARM1 protein and its association with inflammation.
| Phenotype | The association of SARM1 with inflammation | Reference |
|---|---|---|
| Nervous system | ||
| Spinal cord injury (SCI) | The selective removal of SARM1 in neurons and astrocytes enhanced the recovery of behavioral performance following SCI. This effect was attributed to the promotion of neuronal regeneration during the intermediate phase of SCI and a decrease in neuroinflammation during the early phase, achieved by downregulating NF-κB signaling and potentially upregulating HSP70. | 12 |
| Experimental autoimmune encephalomyelitis(EAE) | The SARM1 in astrocytes inhibits the expression of GDNF, leading to neuronal inflammation and demyelination. Upregulation of GDNF in astrocytes suppresses the NF-κB signaling pathway. | 22 |
| Repeated mild closed head injury (rmCHI) | Activation of astroglia and microglia decreased in white matter damage, indicating a reduction in inflammation. | 52 |
| Traumatic injury model | The SARM1-MAPK pathway disrupts the energy balance in axons, leading to ATP depletion before the physical breakdown of the damaged axon. This depletion subsequently triggers calpain activation and results in morphological degradation. Besides, SARM1 knockout significantly reduces the upregulation of Ccl7 and Ccl12 in damaged neurons through the JNK-c-Jun pathway. | 46,47 |
| Nmnat2V98M/R232Q Mutation model | NMNAT2 acts as an inhibitor of SARM1, and studies on NMNAT2 mutant mice have demonstrated a decrease in programmed axonal degeneration. This reduction includes improvements in progressive motor function, reduced peripheral axon loss, and decreased macrophage infiltration, all of which are entirely dependent on the presence of SARM1. | (Dingwall et al. 2022)69 |
| Skin | ||
| Plantar incision | Celastrol pretreatment up-regulates SARM1 expression and inhibits NF-κB signaling pathway activation, which in turn reduces pro-inflammatory cytokines release and pain-related behaviors | 54 |
| Liver | ||
| High fat diet model | SARM1-deletion was found to alleviate the inflammatory response caused by HFD. This was achieved through the inactivation of TLR4/7/9 and NF-κB pathways. Additionally, the deletion of SARM1 led to a reduction in the expressions of inflammation-associated molecules in the hypothalamus of HFD-fed mice. | 21 |
| Liver fibrosis model | In the context of hepatic stellate cells (HSCs), TRPV1 is capable of impeding pro-inflammatory activation by binding to the TIR domain of SARM1. This interaction effectively inhibits NF-κB activation and the subsequent production of pro-inflammatory cytokines. | 2 |
| Pathogen infection | ||
| Klebsiella pneumoniae infection | SARM1 is essential for Klebsiella-induced interleukin-10 (IL-10) production by modulating the p38-type I interferon (IFN) axis, which inhibits the activation of the Klebsiella-induced absent in melanoma 2 (AIM2) inflammasome, thereby reducing IL-1β production and limiting subsequent inflammation. | 55 |
| Mycobacteroides abscessus infection | As a negative regulator of TLR signaling, the low levels of SARM1 plays a role in the upregulated inflammatory responses in patients. | 56 |
| Respiratory syncytial virus(RSV) infection | SARM1 suppression resulted in an uncontrolled immune response to RSV, characterized by increased TRIF expression. High TRIF expression led to a pronounced Th1 response and elevated levels of IFN-γ, which subsequently exacerbated airway inflammation and airway hyperresponsiveness (AHR). | (Long et al. 2015)70, (Liu et al. 2014)57 |
| La Crosse virus (LACV) infection | LACV infection induced SARM1upregulation, which mediated cell death associated with oxidative stress response and mitochondrial damage. | 58 |
| West Nile virus(MNV) infection | Loss of SARM1 linked to increased viral replication, reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. | 59,60 |
| Phenotype | The association of SARM1 with inflammation | Reference |
|---|---|---|
| Nervous system | ||
| Spinal cord injury (SCI) | The selective removal of SARM1 in neurons and astrocytes enhanced the recovery of behavioral performance following SCI. This effect was attributed to the promotion of neuronal regeneration during the intermediate phase of SCI and a decrease in neuroinflammation during the early phase, achieved by downregulating NF-κB signaling and potentially upregulating HSP70. | 12 |
| Experimental autoimmune encephalomyelitis(EAE) | The SARM1 in astrocytes inhibits the expression of GDNF, leading to neuronal inflammation and demyelination. Upregulation of GDNF in astrocytes suppresses the NF-κB signaling pathway. | 22 |
| Repeated mild closed head injury (rmCHI) | Activation of astroglia and microglia decreased in white matter damage, indicating a reduction in inflammation. | 52 |
| Traumatic injury model | The SARM1-MAPK pathway disrupts the energy balance in axons, leading to ATP depletion before the physical breakdown of the damaged axon. This depletion subsequently triggers calpain activation and results in morphological degradation. Besides, SARM1 knockout significantly reduces the upregulation of Ccl7 and Ccl12 in damaged neurons through the JNK-c-Jun pathway. | 46,47 |
| Nmnat2V98M/R232Q Mutation model | NMNAT2 acts as an inhibitor of SARM1, and studies on NMNAT2 mutant mice have demonstrated a decrease in programmed axonal degeneration. This reduction includes improvements in progressive motor function, reduced peripheral axon loss, and decreased macrophage infiltration, all of which are entirely dependent on the presence of SARM1. | (Dingwall et al. 2022)69 |
| Skin | ||
| Plantar incision | Celastrol pretreatment up-regulates SARM1 expression and inhibits NF-κB signaling pathway activation, which in turn reduces pro-inflammatory cytokines release and pain-related behaviors | 54 |
| Liver | ||
| High fat diet model | SARM1-deletion was found to alleviate the inflammatory response caused by HFD. This was achieved through the inactivation of TLR4/7/9 and NF-κB pathways. Additionally, the deletion of SARM1 led to a reduction in the expressions of inflammation-associated molecules in the hypothalamus of HFD-fed mice. | 21 |
| Liver fibrosis model | In the context of hepatic stellate cells (HSCs), TRPV1 is capable of impeding pro-inflammatory activation by binding to the TIR domain of SARM1. This interaction effectively inhibits NF-κB activation and the subsequent production of pro-inflammatory cytokines. | 2 |
| Pathogen infection | ||
| Klebsiella pneumoniae infection | SARM1 is essential for Klebsiella-induced interleukin-10 (IL-10) production by modulating the p38-type I interferon (IFN) axis, which inhibits the activation of the Klebsiella-induced absent in melanoma 2 (AIM2) inflammasome, thereby reducing IL-1β production and limiting subsequent inflammation. | 55 |
| Mycobacteroides abscessus infection | As a negative regulator of TLR signaling, the low levels of SARM1 plays a role in the upregulated inflammatory responses in patients. | 56 |
| Respiratory syncytial virus(RSV) infection | SARM1 suppression resulted in an uncontrolled immune response to RSV, characterized by increased TRIF expression. High TRIF expression led to a pronounced Th1 response and elevated levels of IFN-γ, which subsequently exacerbated airway inflammation and airway hyperresponsiveness (AHR). | (Long et al. 2015)70, (Liu et al. 2014)57 |
| La Crosse virus (LACV) infection | LACV infection induced SARM1upregulation, which mediated cell death associated with oxidative stress response and mitochondrial damage. | 58 |
| West Nile virus(MNV) infection | Loss of SARM1 linked to increased viral replication, reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. | 59,60 |
However, SARM1 can inhibit the expression of inflammatory factors in some pathological models. The catecholaminergic neurotransmitter norepinephrine enhances the expression of IL-17 cytokines and plays a pro-inflammatory role in ulcerative colitis. SARM1 has the function of regulating axonal degeneration and can play an anti-inflammatory role in the enteric nervous system. In a mouse model of dextran sulfate (DSS) -induced colitis, SARM1−/− mice experienced weight loss, shortened colon length, crypt loss, and more severe immune cell infiltration after DSS treatment compared to wild control mice. Since SARM1 is highly expressed not only in neurons, but also in immune cells, it was verified using bone marrow chimera mice. The results show that SARM1, which plays a protective role in colitis, is expressed by neurons and has nothing to do with immune cells53 (Table 1).
SARM1 and liver diseases
SARM1 and capsaicin receptor (TRPV1) work together to inhibit the expression of pro-inflammatory cytokines in stationary HSCS. The mechanism of this anti-inflammatory effect is that TRPV1 interacts with the TIR domain of SARM1 to form a complex that interferes with NF-κB signaling mediated pro-inflammatory HSCS activation and hepatic fibrosis formation.2
In a study of non-alcoholic fatty liver induced by a high fat diet (HFD),21 SARM1-KO significantly attenuated the overexpression of IL-1β, IL-6, TNF-α, and MCP-1 in serum and liver induced by HFD. Further studies showed that the reduction of the above inflammatory factors may be achieved by blocking the TLR4/7/9 and NF-κB pathways. The results also showed that SARM1 deletion improved steatohepatitis and metabolic disorders caused by HFD in mice, and improved liver function. In addition, SARM1-KO also reduced the expression of inflammation-related molecules in the hypothalamus of HFD-fed mice.
SARM1 and skin diseases
In an experiment in which triptolide (CEL) was applied to reduce pain response and neuroinflammation in plantar incision in mice, SARM1 played a role in alleviating neuroinflammation.54 After plantar incision surgery, skin cells can cause neurons to fire through nerve activators, which can lead to neuroinflammation and pain. More and more literatures have reported that the activation of NF-κB is closely related to the production of proinflammatory mediators (such as cytokines, chemokines and enzymes) after surgery, and the production of these proinflammatory mediators is an important cause of pain-related behaviors.61,62 SARM1 inhibits the activation of the NF-κB signaling pathway, reducing pro-inflammatory cytokine release and pain-related behaviors. In this experiment, although CEL was administered to mice with SARM1 deletion before surgery, CEL’s inhibitory effect on NF-κB activity was weakened compared with the control group, and neuroinflammation at the plantar incision of mice was more severe.
SARM1 in infection diseases
Many pathogenic bacterial pathogens carry proteins with TIR NADase activity. The TIR proteins of these pathogens have been shown to inhibit the production of pro-inflammatory factors such as TNF-α and IL-6, as well as the activation of NF-κB, enabling immune escape in the host.63,64 Interestingly, the SARM1 TIR domain also exhibits potential NADase activity, leading to axon energy depletion and negative regulatory effects on the immune system. Phylogenetic analysis suggests that animal SARM1 TIR proteins are more closely related to bacterial TIR proteins than their eukaryotic counterparts.10 This suggests that animal SARM1 TIR may have originated through horizontal gene transfer from bacteria to animals. The mechanism of negative immune regulation may reflect the evolutionarily conserved function of bacterial TIR proteins in suppressing host immune responses.9,10,65
SARM1-related virus infections are mostly neurotropic viruses. Notably, Sarm1 knockout does not affect all pathogen infections,58 but it does exert a unique effect on pathogens that primarily infect the brain, such as neurotropic viruses. This is consistent with the high expression of SARM1 protein in the brain. When Sarm1 is knocked down or its protein expression is reduced, inflammation in brain tissue is weakened, virus infiltration is reduced, and neuronal damage and death are mitigated, demonstrating a protective effect. One prominent example is the La Crosse virus (LACV)58 and vesicular stomatitis virus (VSV).66Upregulation of Sarm1 expression induced by LACV results in excessive reactive oxygen species production through interaction with mitochondrial antiviral signaling proteins, leading to oxidative stress response, neuronal injury, and apoptosis. The protective effect of SARM1 on VSV infection is similar to that of LACV and mainly involves reducing central nervous system injury and cytokine production by non-hematopoietic cells. Interestingly, this protective effect of Sarm1 knockout was not observed in West Nile virus59,60 (MNV) and respiratory syncytial virus57 (RSV) infection, which can be attributed to the immune negative regulatory function of SARM1. Both MNV and RSV require TLR signals to limit infection. Sarm1 knockout inhibits TNF-α synthesis and reduces microglia activation, resulting in increased neuronal death and further aggravating infection symptoms.
However, when the main site of infection was the peripheral blood, SARM1 expression is second only to the brain. Upregulation of Sarm1 expression in pathogen infection significantly inhibits inflammation. Representative examples include mycobacterium abscess56 and Klebsiella pneumoniae (KP).55 Upon KP infection, the host upregulates melanoma 2 inflammasome (AIM2) in a type I IFN-dependent manner to trigger a local immune response against bacterial infection. Meanwhile, KP also upregulates SARM1 expression in a type I IFN-dependent manner and inhibits AIM2 inflammasome activation through direct interaction between SARM1 and AIM2, thereby limiting the production of IL-1b and suppressing further inflammatory responses. Consistent with this, immuno-transcriptome analysis of peripheral blood monocytes derived from clinical patients with Mycobacterium abscessus infection revealed upregulation of proinflammatory cytokines/chemokines and decreased SARM1 expression levels compared to healthy controls.
Conclusion
Based on our understanding of the physiological and pathological functions of SARM1, we now know that maintaining basal levels of SARM1 and increasing its expression under stress conditions may be crucial for promoting mammalian health. SARM1 plays a role in clearing dysfunctional mitochondria and damaged neuronal axons, thereby preventing neuronal death. It is also involved in multiple inflammatory pathways, regulating the release of pro-inflammatory cytokines and influencing pain-related behaviors.
However, the activation of SARM1 is not without potential risks. In the case of a neurotropic virus infection, SARM1 inhibits the activation of inflammatory factors that would otherwise help contain the virus, potentially leading to its spread. Moreover, excessive presence of SARM1 can deplete NAD+ and cause axonal damage, resulting in the death of cells that should have survived. This phenomenon can occur in aging, Parkinson’s disease, and other neurodegenerative conditions. Nevertheless, in most diseases, we still lack a comprehensive understanding of how to balance the potential risks of SARM1 against its numerous adaptive physiological functions. Existing evidence from fruit flies, C. elegans, and mouse models suggests that the primary role of SARM1 may be to promote inflammation and facilitate NAD+ breakdown. However, further research is necessary to determine the specific factors that determine whether SARM1 is beneficial or pathological in more specific disease contexts.
Clearly, we have gained valuable insights from studying SARM1 in model organisms. The main question now is whether these findings can be translated into predictive knowledge about the role of SARM1 in human diseases. Considering the evolutionary conservation of SARM1, its regulation of signaling pathways, and its physiological function, it is possible that such insights can be applied in humans. Nowadays, SARM1 inhibitors are extensively used in preclinical models for treating nerve injuries and diseases. Early treatment with SARM1 inhibitors can prevent the onset and progression of axonal degeneration. Competitive inhibitors, such as nicotinic acid mononucleotide,67 bind to the allosteric site on the N-terminal ARM domain of SARM1, blocking NMN from accessing this site. Non-competitive inhibitors work by intercepting NAD hydrolysis and forming covalent bonds with the reaction product, adenosine diphosphate ribose (ADPR).68 However, attempts to develop neuroprotective treatments for neurodegenerative disorders by targeting SARM1have not yet been clinically successful. Given the strong association between neurodegenerative diseases and axon degeneration, targeting SARM1 NADase presents a promising new approach for the prevention and treatment of infections, cancers, and degenerative diseases. To achieve this, we must deepen our understanding of the signaling control of SARM1, the molecular mechanisms underlying Wallerian degeneration and the mechanistic basis associated with neurodegeneration in SARM1 activation and axonal injury.
Author contributions
Yihan Ye conceived the idea and completed the paper. Fuyong Song provided writing instructors and recommendations.
Funding
None declared.
Conflict of interest statement: None declared.
References
Dingwall CB, Strickland A, Yum SW, Yim AK, Zhu J, Wang PL, Yamada Y, Schmidt RE, Sasaki Y, Bloom AJ, et al. Macrophage depletion blocks congenital SARM1-dependent neuropathy.
Long X, Li S, Xie J, Li W, Zang N, Ren L, Deng Y, Xie X, Wang L, Fu Z, et al. MMP-12-mediated by SARM-TRIF signaling pathway contributes to IFN-γ-independent airway inflammation and AHR post RSV infection in nude mice.
