Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross‐talk act as a linchpin in the events leading to thromboinflammation

Abstract

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.

Kallikrein Cleaves C3 and Activates Complement

“…Once activated, both systems trigger a coordinated immune response that comprises opsonization, phagocytosis, acute and chronic inflammation, vascular permeability, pain, and fever [1,2,5,7]. Here, we have shown that kallikrein (generated from prekallikrein by the induced contact system) activates the complement system by cleaving C3 and factor B, with subsequent formation of an active complement C3 convertase.…”

“…Furthermore, kallikrein activates the fibrinolytic system, and plasminogen is converted to plasmin. The simultaneous activation of all 3 pathways (contact, coagulation, and complement) is a phylogenetic and ancient host response to infection and tissue injury, leading to thromboinflammation [5]. Thus, it is not surprising that the plasma contact and complement systems interact.…”

“…The main regulator of the alternative pathway is complement factor H, whereas that of the classical/lectin pathway is C4b binding protein. Both regulators dissociate C3 convertases and mediate cofactor activity, thereby enabling protease factor I to degrade C3b [5,[7][8][9][10]. Previous studies show that the complement, coagulation, and contact systems interact: thrombin FIXa, FXa, FXIa, and plasmin cleave C3 and C5 [11,12], FXIIf activates the protease C1s of the classical pathway [13], and kallikrein cleaves complement factor B [14].…”

Innate immune responses to trauma

“…Activation of the sympathoadrenal system during hemorrhagic shock induces profound vasoconstriction that is counteracted by the release of vasodilatory nitric oxide from stressed and damaged endothelial cells, which leads to microcirculatory disturbances. The coagulation and complement systems and interacting platelets are rapidly activated after trauma 18,19,51 , which results in a stemming of hemorrhage and protection against invading bacteria. Of note, injured patients prospectively followed for the development of either a ‘sterile’ systemic inflammatory response or sepsis exhibited differential expression of plasma proteins in each sequela.…”

“…Thrombin, in turn, activates fibrinogen to form thrombi with platelets and also activates endothelial cells, which leads to the endothelial release of cytokines, cell contraction, enhancement of permeability and expression of adhesion molecules 48 . The consequences are vascular inflammation, (micro)perfusion disturbances and hypoxia, all of which aggravate the thromboinflammatory response 51,55 . Trauma-generated DAMPs (for example, mitochondrial DNA) and ROS also induce the endothelial expression of adhesion molecules that facilitate leukocyte adhesion 56 , which promotes extravasation into injured tissue that is controlled by vascular endothelial cadherin 57 .…”