To review the role of the Toll-like receptors (TLR) as the principal sensors used by the innate immune system in the context of the pathologic processes underlying sepsis and septic shock.
Through the Toll-like receptors, macrophages and other defensive cells “see” endotoxin (TLR4), peptidoglycan (TLR2), and bacterial DNA (TLR9). Representatives of the family predated the divergence of plants and animals and, at that time, had already acquired a defensive function. The strengths and liabilities of the innate immune system, which defends against infection and which also may cause shock and death, are rooted in its ancient origins. In the current era of shock research, the nature of the signals that Toll-like receptors transduce and the effects of genetic variation on microbial sensing are two major challenges.
From the Department of Immunology, The Scripps Research Institute, La Jolla, CA.
Presented, in part, at the Margaux Conference on Critical Illness, Margaux, France, November 8–12, 2000.
Address requests for reprints to: Bruce Beutler, MD, The Scripps Research Institute, Department of Immunology, IMM-31, 10550 N. Torrey Pines Road, La Jolla, CA 92037. E-mail: email@example.com
The possibility of blocking Toll-like receptor signal transduction by means of drugs that directly interact with the Toll/IL-1-related domain of different TLRs, or perhaps with the Toll/IL-1-related domain of the transducer MyD88, also beckons as a possible intervention to mitigate the untoward consequences of global innate immune activation.