Thrombin Promotes Macrophage Polarization into M1-Like Phenotype to Induce Inflammatory
Responses
Macrophages are highly versatile cells of the innate immune system with a high degree
of plasticity. In response to their respective tissue environment they can adopt various
functionally different phenoytpes or polarization states. In response to inflammatory
stimuli macrophages polarize into proinflammatory M1 cells whereas anti-inflammatory
stimuli induce alternative polarization into anti-inflammatory, reparative M2 macrophages.
Accumulating evidence supports the notion that macrophages represent a cellular link
between inflammation and cardiovascular pathologies such as atherogenesis and thrombosis.[1] On the other hand, thrombin is not only the central protease in the coagulation
cascade but among various other functions also modulates inflammatory processes.[2] In this issue of Thrombosis and Haemostasis, López-Zambrano et al have revealed yet another link between the coagulation system
and inflammation modulated by cells of the innate immune system.[3] The authors show in vitro that thrombin induces macrophages to polarize toward an
M1 phenotype that is characterized by the expression of proinflammatory cytokines
and chemokines. This effect of thrombin was at least in part mediated via protease
activated receptor-1 (PAR-1). Interestingly, heat denatured, enzymatically inactive
thrombin was still effective in inducing a proinflammatory response in macrophages
suggesting a pathway independent of PAR-1, which has to be proteolytically cleaved
to induce signal transduction. Taken together, this study provides evidence that in
a prothrombotic microenvironment, formed thrombin is not only able to promote thrombus
formation but also can shift the setting toward inflammation by affecting the polarization
state of macrophages. Interestingly, proinflammatory M1 macrophages in contrast to
anti-inflammatory M2 macrophages are proteolytically highly active.[4] The kinetics and dynamics of macrophage polarization toward a particular phenotype
have mainly been assessed in in vitro studies. Thus, future investigations addressing
these research questions in vivo are highly relevant.
