SARM1: a key multifaceted component in immunoregulation, inflammation and neurodegeneration

Abstract

The downstream signaling pathways of TLR activation involve a family of adaptor proteins, including MYD88, TIRAP, TRIF, TRAM, and SARM1. The first four proteins stimulate inflammatory and antiviral responses, playing crucial roles in innate immunity against various pathogens. In contrast, SARM1 promotes immunity to microorganisms in invertebrate animals independently of TLRs, and negatively regulates inflammatory responses in metazoan organisms. SARM1 inhibits TRIF, reduces the activation of various inflammasomes, and induces mitochondrial damage and cell death to eliminate hyperactivated cells. This regulation is essential to ensure timely control of immune responses and to prevent excessive inflammation. Recently, it was discovered that SARM1 can hydrolyze NAD, a critical component of cellular metabolism. The reduction of NAD levels by SARM1 is linked to the progression of Wallerian degeneration following neuronal injury and may also play a role in the immunoregulation of lymphoid and myeloid cells. Since SARM1 can be pharmacologically modulated, it presents promising opportunities for developing treatments for inflammatory and neurodegenerative diseases.

Keywords: cell death; immunometabolism; immunoregulation; innate immunity; neurodegenerative disease.

Figure 1

The action of mammalian SARM1 and its C. elegans ortholog TIR-1 in the immune response to pathogens. Pathogen presence triggers an inflammatory response mediated by TIR-1 independently of Toll-1. The mechanism by which TIR-1 is associated with sequential phosphorylation of NSY-1, SEK-1, and PMK-1 remains unknown. PMK-1 phosphorylates ATF-7, facilitating its translocation to promote the expression of inflammatory response genes. In mammalian cells, TLR activation promotes an inflammatory or antiviral response. Signal transduction from the plasma/endosomal membrane to the nucleus relies on adaptor proteins such as MYD88, TRIF, TRAM, and TIRAP. These adaptors interact via the TIR domain with TLRs and activate TRAF3 or TRAF6, important proteins for NF-kB and IRF3/7 activation. SARM1 interacts with TLR adaptor proteins through its TIR domain, inhibiting their recruitment to TLRs and blocking their signaling. Figure created with BioRender.com.

Figure 2

Schematic representation of SARM1 structure, its activation mechanism, and enzymatic activity. SARM1 consists of an autoinhibitory ARM domain, two tandem SAM domains responsible for SARM1 multimerization, a TIR domain with the NADase activity residue, and a mitochondrial membrane anchoring tag. The NMN/NAD+ ratio determines SARM1 activation status. A decrease in the ratio favors NAD+ binding to the ARM domains of SARM1 multimers, maintaining separation between the TIR domains of SARM1 multimers and inhibiting NAD+ hydrolysis, a process that promotes axonal survival in neurodegenerative diseases. A high ratio enables NMN binding to the ARM domain, induces conformational changes in the multimer, and brings its TIR domains closer to creating the allosteric NAD+ cleavage site, a process associated with neuronal degeneration progression after injury. (C) The catalytic activity residue of SARM1's TIR domain on NAD+ is located in the vicinity of amino acid 642. When activated, SARM1 degrades NAD+ into Nam and ADRP, the latter of which can still be cyclized to form cADRP. Figure created with BioRender.com.

Figure 3

Control of different cell death pathways by SARM1. Upon its activation, NLRP3 and AIM2 inflammasomes recruit the adaptor protein ASC to form cleavage and activation platforms for caspase-1, a protease responsible for the maturation of pro-inflammatory cytokines IL-1β and IL-18, as well as for the cleavage of GSDMD. The N-terminal fragments of GSDMD form pores in the plasma membrane to promote the release of matured cytokines from the inflammasome and may lead the cell to pyroptosis. SARM1 can interact with NLRP3 and AIM2 molecules and prevent the formation of both inflammasomes. However, SARM1 can induce apoptosis or even pyroptosis. It is associated with the phosphorylation of pro-apoptotic proteins such as BAD and the reduction in the expression of proteins that maintain mitochondrial homeostasis, such as the BCL family proteins. This phenomenon induces increased ROS production to promote apoptotic cell death and, depending on the stimulus, to promote pyroptosis of cells to prevent the formation of hyperactive cells. Figure created with BioRender.com.

Figure 4

The importance of SARM1 in pathogen tolerance and resistance. SARM1 acts in different ways in invertebrates. In C. elegans, TIR-1 promotes inflammation and is essential for resistance to infections by microorganisms, while in human cells, SARM1 is associated with tolerance, aiming to prevent the exacerbation of the immune response and maintain the integrity of the host tissues. Figure created with BioRender.com.