It is well known that platelets, aside from regulating hemostasis, play an important role in inflammation-associated conditions like sepsis, viral infections, and atherosclerosis. In the latter, platelets not only form occlusive thrombi at lesions, but also play a role in the initiation of the disease by depositing activating molecules such as cytokines on the developing plaque. Although the mechanism by which platelet aggregation leads to occlusion is well-defined, the role of platelets in lesion initiation and progression is poorly understood and thus remains a gap in our knowledge. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a receptor exclusively found on megakarocytes and platelets that has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface along with p-selectin from the α-granules. Studies using the treml1−/− mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms and therefore should play a role in the development of atherosclerosis. Our original hypothesis was that evaluation of atherosclerosis lesions in the treml1−/− mouse would demonstrate fewer lesions and hence, a similar phenotype as the psel−/− mouse. Evaluation of 50 week old mice fed a chow diet surprisingly revealed spontaneous lesions in C57Bl/6 treml1−/− mice. Subsequent evaluation of cholesterol levels in treml1−/−mice on an atherogenic diet for four weeks demonstrated that they have significantly higher cholesterol levels when compared to WT mice. To evaluate atherosclerosis progression in TLT-1 deficiency, we developed the apoE−/−/treml1−/− double knockout mice and assessed lesion development after a four weeks atherogenic diet. Our results demonstrate that double null mice have exacerbated lesions when compared to the apoE −/− mice. Accordingly, 50 week old double null mice fed a chow diet also have larger atherosclerotic lesions in the aortic sinus than apoE −/− mice. These results clearly support a role for TLT-1 in dampening the progression of atherosclerosis. Current data from our laboratory suggest that TLT-1 may affect leukocyte function, therefore based on our model that TLT-1 deficiency leads to a heighted inflammatory state we hypothesized that treml1−/− mice will demonstrate greater leukocyte recruitment into the injured vessel wall, leading to greater deposition of factors that recruit more platelets and macrophages that later become foam cells. To delineate the mechanism by which TLT-1 affects atherosclerosis progression, we have evaluated neutrophil and monocyte infiltration into the vessel wall of the aortic sinus after four weeks atherogenic diet. The current state of our investigation is reported here.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.