Department of Medicine, John Hopkins University School of Medicine, Baltimore, USA.
J Inflamm (Lond). 2013 May 30;10(1):23. doi: 10.1186/1476-9255-10-23.
The extracellular matrix plays a critical role in insuring tissue integrity and water homeostasis. However, breakdown products of the extracellular matrix have emerged as endogenous danger signals, designed to rapidly activate the immune system against a potential pathogen breach. Type I interferons play a critical role in the immune response against viral infections. In the lungs, hylauronan (HA) exists as a high molecular weight, biologically inert extracellular matrix component that is critical for maintaining lung function. When lung tissue is injured, HA is broken down into lower molecular weight fragments that alert the immune system to the breach in tissue integrity by activating innate immune responses. HA fragments are known to induce inflammatory gene expression via TLR-MyD88-dependent pathways.
Primary peritoneal macrophages from C57BL/6 wild type, TLR4 null, TLR3 null, MyD88 null, and TRIF null mice as well as alveolar and peritoneal macrophage cell lines were stimulated with HA fragments and cytokine production was assessed by rt-PCR and ELISA. Western blot analysis for IRF3 was preformed on cell lysates from macrophages stimulate with HA fragments
We demonstrate for the first time that IFNβ is induced in murine macrophages by HA fragments. We also show that HA fragments induce IFNβ using a novel pathway independent of MyD88 but dependent on TLR4 via TRIF and IRF-3.
Overall our findings reveal a novel signaling pathway by which hyaluronan can modulate inflammation and demonstrate the ability of hyaluronan fragments to induce the expression of type I interferons in response to tissue injury even in the absence of viral infection. This is independent of the pathway of the TLR2-MyD88 used by these matrix fragments to induce inflammatory chemokines. Thus, LMW HA may be modifying the inflammatory milieu simultaneously via several pathways.
细胞外基质在确保组织完整性和水稳态方面起着关键作用。然而，细胞外基质的分解产物已成为内源性危险信号，旨在迅速激活免疫系统以应对潜在的病原体入侵。I 型干扰素在抗病毒感染的免疫反应中起着关键作用。在肺部，透明质酸（HA）作为一种高分子量、生物惰性的细胞外基质成分存在，对于维持肺功能至关重要。当肺组织受损时，HA 被分解成低分子量片段，通过激活先天免疫反应，向免疫系统发出组织完整性受损的警报。已知 HA 片段通过 TLR-MyD88 依赖途径诱导炎症基因表达。
用 HA 片段刺激 C57BL/6 野生型、TLR4 缺失型、TLR3 缺失型、MyD88 缺失型和 TRIF 缺失型小鼠的原代腹腔巨噬细胞以及肺泡和腹腔巨噬细胞系，通过 rt-PCR 和 ELISA 评估细胞因子的产生。用 HA 片段刺激巨噬细胞的细胞裂解物进行 IRF3 的 Western blot 分析。
我们首次证明 HA 片段可诱导小鼠巨噬细胞产生 IFNβ。我们还表明，HA 片段通过 TLR4 依赖性 TRIF 和 IRF-3 诱导 IFNβ，该途径不依赖于 MyD88。
总的来说，我们的研究结果揭示了一种新型信号通路，通过该通路，透明质酸可调节炎症，并证明了透明质酸片段即使在没有病毒感染的情况下，也能诱导 I 型干扰素的表达，以响应组织损伤。这独立于这些基质片段用于诱导炎症趋化因子的 TLR2-MyD88 途径。因此，LMW HA 可能通过几种途径同时改变炎症环境。
