Many of the ligands for Toll-like receptors (TLRs) are unique to microorganisms, such that receptor activation unequivocally indicates the presence of something foreign. However, a subset of TLRs recognizes nucleic acids, which are present in both the host and foreign microorganisms. This specificity enables broad recognition by virtue of the ubiquity of nucleic acids but also introduces the possibility of self-recognition and autoinflammatory or autoimmune disease. Defining the regulatory mechanisms required to ensure proper discrimination between foreign and self-nucleic acids by TLRs is an area of intense research. Progress over the past decade has revealed a complex array of regulatory mechanisms that ensure maintenance of this delicate balance. These regulatory mechanisms can be divided into a conceptual framework with four categories: compartmentalization, ligand availability, receptor expression and signal transduction. In this Review, we discuss our current understanding of each of these layers of regulation.

Toll 样受体 (TLR) 的许多配体是微生物所独有的，因此受体激活明确表明存在外来物质。然而，TLR 的一个子集识别存在于宿主和外来微生物中的核酸。由于核酸的普遍存在，这种特异性能够实现广泛的识别，但也引入了自我识别和自身炎症或自身免疫疾病的可能性。定义确保通过 TLR 正确区分外源核酸和自身核酸所需的调节机制是一个深入研究的领域。过去十年的进展揭示了一系列复杂的监管机制，以确保维持这种微妙的平衡。这些监管机制可以分为四类概念框架：区室化、配体可用性、受体表达和信号转导。在这篇评论中，我们讨论了我们目前对这些监管层的理解。