Medvedev Andrei E, Sabroe Ian, Hasday Jeffrey D, Vogel Stefanie N
Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), Baltimore, Maryland 21201, USA.
J Endotoxin Res. 2006;12(3):133-50. doi: 10.1179/096805106X102255.
Many host cell types, including endothelial and epithelial cells, neutrophils, monocytes, natural killer cells, dendritic cells and macrophages, initiate the first line of defense against infection by sensing conserved microbial structures through Toll-like receptors (TLRs). Recognition of microbial ligands by TLRs induces their oligomerization and triggers intracellular signaling pathways, leading to production of pro- and anti-inflammatory cytokines. Dysregulation of the fine molecular mechanisms that tightly control TLR signaling may lead to hyperactivation of host cells by microbial products and septic shock. A prior exposure to bacterial products such as lipopolysaccharide (LPS) may result in a transient state of refractoriness to subsequent challenge that has been referred to as 'tolerance'. Tolerance has been postulated as a protective mechanism limiting excessive inflammation and preventing septic shock. However, tolerance may compromise the host's ability to counteract subsequent bacterial challenge since many septic patients exhibit an increased incidence of recurrent bacterial infection and suppressed monocyte responsiveness to LPS, closely resembling the tolerant phenotype. Thus, by studying mechanisms of microbial tolerance, we may gain insights into how normal regulatory mechanisms are dysregulated, leading ultimately to microbial hypo-responsiveness and life-threatening disease. In this review, we present current theories of the molecular mechanisms that underlie induction and maintenance of 'microbial tolerance', and discuss the possible relevance of tolerance to several infectious and non-infectious diseases.
许多宿主细胞类型，包括内皮细胞、上皮细胞、中性粒细胞、单核细胞、自然杀伤细胞、树突状细胞和巨噬细胞，通过Toll样受体（TLR）感知保守的微生物结构，从而启动抵御感染的第一道防线。TLR识别微生物配体可诱导其寡聚化并触发细胞内信号通路，导致促炎和抗炎细胞因子的产生。紧密控制TLR信号传导的精细分子机制失调可能导致宿主细胞被微生物产物过度激活和感染性休克。先前接触细菌产物如脂多糖（LPS）可能导致对后续刺激产生短暂的不应状态，即所谓的“耐受”。耐受被认为是一种保护机制，可限制过度炎症并预防感染性休克。然而，耐受可能会损害宿主应对后续细菌挑战的能力，因为许多脓毒症患者反复发生细菌感染的发生率增加，且单核细胞对LPS的反应性受到抑制，这与耐受表型非常相似。因此，通过研究微生物耐受机制，我们可能深入了解正常调节机制是如何失调的，最终导致对微生物反应性降低和危及生命的疾病。在这篇综述中，我们介绍了目前关于“微生物耐受”诱导和维持的分子机制的理论，并讨论了耐受与几种感染性和非感染性疾病的可能相关性。
