Oliveira Samuel Dos Santos, Honório da Silva João Vinícius, Vieira Raquel de Souza, Moreira Luís Felipe Serra, Bandeira Pedro Henrique Araújo, Ramos Beatriz Leocata, Silva Marco Antônio Ataíde, Câmara Niels Olsen Saraiva
Department of Biochemistry and Immunology, Ribeirão Preto Medical School - FMRP of the University of São Paulo - USP, Ribeirão Preto, Brazil.
Department of Immunology, Institute of Biomedical Science - ICB of the University of São Paulo - USP, São Paulo, Brazil.
Front Immunol. 2025 May 13;16:1521364. doi: 10.3389/fimmu.2025.1521364. eCollection 2025.
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.
Toll样受体（TLR）激活的下游信号通路涉及一类衔接蛋白，包括髓样分化因子88（MYD88）、TIR结构域衔接蛋白（TIRAP）、TIR结构域衔接蛋白诱导干扰素β（TRIF）、TRIF相关衔接分子（TRAM）和 sterile alpha and TIR motif-containing protein 1（SARM1）。前四种蛋白刺激炎症和抗病毒反应，在针对各种病原体的固有免疫中发挥关键作用。相比之下，SARM1在无脊椎动物中独立于TLR促进对微生物的免疫，并在后生动物中负向调节炎症反应。SARM1抑制TRIF，减少各种炎性小体的激活，并诱导线粒体损伤和细胞死亡以清除过度活化的细胞。这种调节对于确保及时控制免疫反应和防止过度炎症至关重要。最近，发现SARM1可以水解烟酰胺腺嘌呤二核苷酸（NAD），这是细胞代谢的关键成分。SARM1导致的NAD水平降低与神经元损伤后沃勒变性的进展有关，也可能在淋巴细胞和髓细胞的免疫调节中起作用。由于SARM1可以进行药理学调节，它为开发炎症和神经退行性疾病的治疗方法提供了有前景的机会。
