Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions, and it is an essential mediator of death in sepsis. However, the ligand for TREM-1 has not been fully identified. Previous research identified a natural ligand of TREM-1 distributed on platelets that contributed to the development of sepsis. However, the exact signal for TREM-1 recognition remains to be identified. Here, we identified actin as a TREM-1-interacting protein on platelets and found that recombinant actin could interact with recombinant TREM-1 extracellular domain directly. Furthermore, actin co-localized with TREM-1 on the surface of activated mouse macrophage RAW264.7 cells interacting with platelets. In addition, recombinant actin could enhance the inflammatory response of macrophages from wt mice but not from trem1−/− mice, and the enhancement could be inhibited by LP17 (a TREM-1 inhibitor) in a dose-dependent manner. Importantly, extracellular actin showed co-localization with TREM-1 in lung tissue sections from septic mice, which suggested that TREM-1 recognized actin during activation in sepsis. Therefore, the present study identified actin as a new ligand for TREM-1 signaling, and it also provided a link between both essential regulators of death in sepsis.
Highlights
Sepsis is a progressive systemic inflammatory response syndrome associated with multiorgan dysfunction caused by overwhelming infection1
To further identify which cell expresses the ligand for Triggering receptor expressed on myeloid cells-1 (TREM-1) during sepsis, the rTREM-1, which could interfere with the signaling [19], was labeled with Cy5.5-NHS-Ester to identify which cells provided the ligand
It was very interesting that rTREM-1 could recognize Ly-6G+ cells during sepsis (Figure 1B), and platelets interacting with neutrophils may partially account for this localization [23, 24]
Summary
Sepsis is a progressive systemic inflammatory response syndrome associated with multiorgan dysfunction caused by overwhelming infection. Despite decades of research and advances in clinical management, morbidity and mortality from sepsis remain substantial and have shown only modest improvements [1], and it is still the leading cause of death in critical care units [2]. Damage-associated molecular patterns (DAMPs) are a kind of activator and contribute to the essential development of sepsis. Actin Is Ligand For TREM-1 extracellular actin is associated with various severe inflammation [4], but it remains to be elucidated how extracellular actin activates the inflammatory signaling
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