Australian Regenerative Medicine Institute (ARMI), Monash University, Melbourne, Victoria, Australia.
The Research Institute of Molecular Pathology (IMP), Vienna, Austria.
Dev Dyn. 2022 Jun;251(6):988-1003. doi: 10.1002/dvdy.340. Epub 2021 Apr 8.
Efficient wound healing or pathogen clearance both rely on balanced inflammatory responses. Inflammation is essential for effective innate immune-cell recruitment; however, excessive inflammation will result in local tissue destruction, pathogen egress, and ineffective pathogen clearance. Sterile and nonsterile inflammation operate with competing functional priorities but share common receptors and overlapping signal transduction pathways. In regenerative organisms such as the salamander, whole limbs can be replaced after amputation while exposed to a nonsterile environment. In mammals, exposure to sterile-injury Damage Associated Molecular Patterns (DAMPS) alters innate immune-cell responsiveness to secondary Pathogen Associated Molecular Pattern (PAMP) exposure.
Using new phospho-flow cytometry techniques to measure signaling in individual cell subsets we compared mouse to salamander inflammation. These studies demonstrated evolutionarily conserved responses to PAMP ligands through toll-like receptors (TLRs) but identified key differences in response to DAMP ligands. Co-exposure of macrophages to DAMPs/PAMPs suppressed MAPK signaling in mammals, but not salamanders, which activate sustained MAPK stimulation in the presence of endogenous DAMPS.
These results reveal an alternative signal transduction network compatible with regeneration that may ultimately lead to the promotion of enhanced tissue repair in mammals.
高效的伤口愈合或病原体清除都依赖于平衡的炎症反应。炎症对于有效的先天免疫细胞募集至关重要；然而，过度的炎症会导致局部组织破坏、病原体逃逸和无效的病原体清除。无菌性和非无菌性炎症的作用具有相互竞争的功能优先级，但它们共享共同的受体和重叠的信号转导途径。在再生生物体（如蝾螈）中，肢体可以在暴露于非无菌环境下被截肢后重新生长。在哺乳动物中，无菌性损伤相关分子模式（DAMPs）的暴露会改变先天免疫细胞对二次病原体相关分子模式（PAMPs）暴露的反应性。
我们使用新的磷酸化流式细胞术技术来测量单个细胞亚群的信号转导，比较了老鼠和蝾螈的炎症反应。这些研究表明，通过 Toll 样受体（TLRs）对 PAMP 配体存在进化保守的反应，但对 DAMP 配体的反应存在关键差异。巨噬细胞同时暴露于 DAMPs/PAMPs 会抑制哺乳动物中的 MAPK 信号转导，但不会抑制蝾螈中的 MAPK 信号转导，因为在存在内源性 DAMPs 的情况下，蝾螈会激活持续的 MAPK 刺激。
这些结果揭示了一种与再生兼容的替代信号转导网络，它可能最终导致哺乳动物中增强组织修复的促进。
