In this issue of Blood, Iqbal et al shed new light on how the procoagulant potential of monocytes/macrophages is controlled by the hitherto unsuspected mechanism modulating the fate of tissue factor (TF) messenger (m)RNA.1
Monocytes, macrophages, and their precursors are cellular mavericks programmed to travel in blood and across tissue barriers to sites of infection, inflammation, injury, and repair.2 This property requires a precise, timely, and localized expression of different functional aptitudes. A startling example of this is the ability of monocytes to enter the circulating blood while effectively “managing” their relationship with the coagulation system.2
Contact with blood can be risky. Monocytes possess the intrinsic potential to activate clotting through expression of TF, the cell surface receptor for the coagulation factor (F)VII/VIIa and potent trigger of the coagulation cascade.3 If monocytes were to express active TF in an unscheduled or exuberant manner, the consequences could be catastrophic, resulting in uncontrolled intravascular activation of clotting processes, as observed in sepsis.4
The remarkable feature of the hemostatic system is its ability to maintain the systemic liquidity of the circulating blood while being able to locally “solidify” blood components to plug up the site of a vascular injury by clots composed of fibrin and platelets. This is accomplished, in part, by the physical separation of latent clotting factors (zymogens) and their potential activators, such as procoagulant surfaces of extracellular matrix and TF expressed by cells outside of the vascular lumen.3 Cells that must come into contact with the circulating blood either shut down their TF transcription (endothelial cells), or control TF activity through a repertoire of plausible but still poorly understood mechanisms, including downregulation of TF gene expression, intracellular retention, conformational inactivation (encryption), presence of inhibitors (TF pathway inhibitor), alternative splicing, and other events that may prevent the contact between TF and FVIIa (see figure).
Disruption of any of these barriers, either through physical (injury) or functional (infection) insults, brings the “critical masses” of TF and FVIIa into proximity, resulting in the explosive but usually self-contained chain of coagulation events that result in thrombin activation and formation of hemostatic clots.3 Notably, TF/FVIIa complexes also possess the ability to generate intracellular signals that “inform” TF-expressing cells about their contact with the clotting blood. This process activates cellular programs required for tissue “cleansing” through inflammation and for their repair involving angiogenesis and wound closure.5 Indeed, the coagulation system has evolved over 450 million years to initially act as a primordial mechanism to trap and contain infectious agents6 and has since retained its links to inflammation and wound healing in higher organisms.2
Not surprisingly, macrophages/monocytes, the cellular “masterminds” of inflammation, are also the main source of TF in the circulating blood.4 TF is expressed after macrophage activation through contact with infectious agents and their products such as bacterial lipopolysaccharide (LPS), as well as chemokines and cytokines.2 This exposure leads to mobilization of the TF coagulant potential, both on the cellular surfaces and through emission of microparticles, fragments of the plasma membrane (also known as extracellular vesicles) that could transfer TF to platelets and endothelial cells.4 These responses leading to formation of clots physically protect the damaged and infected tissue2 and make profound biological sense, but only when they occur in a localized and timely manner. How do macrophages “know” what is the right time, order, and circumstance to express active TF?
Due to the destructive potential of blood vessel perturbations, many powerful vascular regulators, including TF, vascular endothelial growth factor, and several others,7 must be precisely titrated by their expressing cells through several levels of molecular control (see figure). Accordingly, the regulation of TF/F3 (coagulation factor 3 gene) transcription has been extensively studied,3 but relatively little is known about the posttranscriptional processing of TF mRNA, with the possible exception of a limited number of studies exploring the role of microRNA in cancer cells.8,9 This gap is surprising, because the availability of the functional mRNA is the important step in control of the levels of bioactive TF protein on the cell surface.
In this regard, the findings of Iqbal et al1 represent a significant breakthrough. While investigating the little-known molecular member of the PARP family of enzymes known as PARP-14,10 these authors noted a marked upregulation of TF mRNA in Parp-14−/− mice, especially in their bone marrow–derived macrophages treated with bacterial LPS. Thus, PARP-14 must represent a new control element acting at the level of TF transcript. Indeed, the study reveals that PARP-14 binds to the 3′ untranslated region of the TF mRNA through the AU (sequence)-rich element. In so doing, PARP-14 forms a complex with TTP, another posttranscriptional regulatory protein, and this event selectively accelerates the decay of the TF mRNA. This mechanism cooperates with the effects of microRNA binding sites, collectively resulting in reduced TF expression and procoagulant activity.
This is an unsuspected finding, and one that is both mechanistically fascinating and potentially important. It is fascinating because PARP-14 decouples TF regulation from other TTP targets such as tumor necrosis factor-α mRNA and thereby provides a “timing device” for delivery of different functional components of the macrophage activation program (coagulant and inflammatory). This finding is also potentially important because in Parp-14−/− mice, the experimental thrombosis is exacerbated in vivo due to excessive production of TF.
This study raises several novel questions that may impact how the procoagulant potential of macrophages (possibly other cells) is understood and confronted in the clinic. How is the PARP-14/TTP pathway regulated in various procoagulant settings such as sepsis, venous thromboembolism, or cancer? Is PARP-14 deregulation a part of disease pathogenesis? What is the impact of these processes on TF signaling, angiogenesis, and other functions? If the PARP-14 pathway can be therapeutically modulated, then when, how, and to what end would this be desirable? While we await answers, we may take a moment to marvel about the intricacies of hemostatic mechanisms and the power of the science able to unravel them.
Conflict-of-interest disclosure: The author declares no competing financial interest.
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