Granzyme B: a new crossroad of complement and apoptosis.
ABSTRACT In response to severe tissue trauma, several "molecular danger" sensing and signaling pathways are activated, especially the complement and the apoptosis cascade. Although possible crossroads between both systems have been proposed, little is known about the underlying molecular interactions. In this study a new interaction interface is presented for C3a and C5a generation by the pro-apoptotic factor granzyme B. In vitro incubation of the central human complement components C3 and C5 with the serine protease granzyme B resulted in a concentration-dependent production of the anaphylatoxins C3a and C5a. The so generated anaphylatoxin C5a was chemotactic active for isolated human neutrophils. In a translational approach, intracellular granzyme B concentration in leukocytes was determined early after severe tissue trauma. In comparison to healthy volunteers, multiple injured patients (less than one hour after trauma, Injury Severity Score > 18, n = 5) presented a significant increase in granzmye B levels in neutrophils and lymphocytes. Thus, tissue trauma is associated with early activation of both, the complement and apoptosis system. The present data suggest a new form of interaction between the complement and the apoptosis system on the level of granzyme B that is capable to generate C3a and C5a independently of the established complement proteases.
- SourceAvailable from: Martin Kolev[Show abstract] [Hide abstract]
ABSTRACT: Complement is traditionally known to be a system of serum proteins that provide protection against pathogens through direct cell lysis and the mobilization of innate and adaptive immunity. However, recent work indicates that the complement system has additional physiological roles beyond those in host defence. In this Opinion article, we describe the new modes and locations of complement activation that enable it to interact with other cell effector systems, such as growth factor receptors, inflammasomes and metabolic pathways. We propose that the location of complement activation dictates its function.Nature Reviews Immunology 11/2014; · 33.84 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Complement and the kallikrein-kinin cascade system are both activated in injured tissues. Little is known about their partnership in the immunopathogenesis of Chagas disease, the chronic infection caused by the intracellular protozoan Trypanosoma cruzi. In this study, we show that pharmacological targeting of the C5a receptor (C5aR) or the bradykinin B2 receptor (B2R) inhibited plasma leakage in hamster cheek pouch topically exposed to tissue culture trypomastigotes (TCTs). Further, angiotensin-converting enzyme inhibitors potentiated TCT-evoked paw edema in BALB/c, C57BL/6, and C5-deficient A/J mice through activation of joint pathways between C5aR/B2R or C3aR/B2R. In addition to generation of C5a and kinins via parasite-derived cruzipain, we demonstrate that macrophages internalize TCTs more efficiently through joint activation of C5aR/B2R. Furthermore, we found that C5aR targeting markedly reduces NO production and intracellular parasitism in macrophages. We then studied the impact of C5aR/B2R cross-talk in TCT infection on the development of adaptive immunity. We found that IL-12p40/70 expression was blunted in splenic dendritic cells by blocking either C5aR or B2R, suggesting that codominant signaling via C5aR and B2R fuels production of the Th1-polarizing cytokine. Finally, we assessed the impact of kinins and C5a liberated in parasite-laden tissues on Th cell differentiation. As predicted, BALB/c mice pretreated with angiotensin-converting enzyme inhibitors potentiated IFN-γ production by Ag-specific T cells via C5aR/B2R cross-talk. Interestingly, we found that B2R targeting upregulated IL-10 secretion, whereas C5aR blockade vigorously stimulated IL-4 production. In summary, we describe a novel pathway by which C5aR/B2R cross-talk couples transendothelial leakage of plasma proteins to the cytokine circuitry that coordinates antiparasite immunity.Journal of immunology (Baltimore, Md. : 1950). 09/2014;
- [Show abstract] [Hide abstract]
ABSTRACT: Treatment guidelines and management principles of polytrauma patients are largely derived from experience, supplemented by the results of few clinical studies. Their clinical impact on survival outcome is rarely scientifically evaluated. Hence, research algorithms need to be developed which enable a rapid and profound reevaluation of the current treatment strategies in polytrauma care and which provide a solid basis for the assessment of future treatment options. Such new concepts might include a more individualized approach and a better identification of operative windows for early definitive care. Since polytrauma results in a complex physiological and immunological disorder, which is additionally influenced by multiple confounding variables, it is challenging to establish such novel algorithms by clinical research only. In this regard, the well defined parameters in valid basic science models can provide a solid base for evaluating current concepts and investigating future treatment options. Here we have analyzed the contribution of basic science to well-established concepts in polytrauma care, such as the management of trauma induced coagulopathy or the damage control orthopedics concept. Many of these ideas moved from previous basic science activities to clinical studies but in many cases the direct effects of basic science on clinical trials or even clinical management strategies often remain elusive. Nevertheless, the knowledge which is created on a daily basis by basic science studies acts as an invaluable data pool, which can be accessed and combined for the clinical researcher to develop and address clinically relevant questions, providing them with a comprehensive pool of information to carefully plan and conduct their clinical trials. This may then subsequently lead to the development of new management principles for polytrauma patients.European Journal of Trauma and Emergency Surgery 06/2011; 38(3):231-239. · 0.38 Impact Factor