Abstract
Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1β, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.
Highlights
Cytokine storm (CS), the most intense manifestation of cytokine release syndrome (CRS), is a dysregulated hyperactive immune response characterized by the release of a variety of mediators including but not limited to interleukins, chemokines, interferons, tumor-necrosis factor and other white blood cell (WBC) mediators which, unlike in physiological inflammatory responses, can damage the host
The simultaneous and correlating rises of C5a and Bb (Figure 1B) indicates that formation of the most effective anaphylatoxin is primarily due to complement activation via the alternative pathway in the case of zymosan and AmBisome
The second series confirmed these changes for zymosan (Figure 1C) and AmBisome (Figure 1D) with the additional information that C3a, C4a and Ba increased and that the levels of most activation markers decreased after 6 h incubation, except C4a
Summary
Cytokine storm (CS), the most intense manifestation of cytokine release syndrome (CRS), is a dysregulated hyperactive immune response characterized by the release of a variety of mediators including but not limited to interleukins, chemokines, interferons, tumor-necrosis factor and other white blood cell (WBC) mediators which, unlike in physiological inflammatory responses, can damage the host They are produced as a consequence of severe adverse effect of some monoclonal antibodies and CAR-T-cell therapies [1, 2], and came to the focus of world-wide attention as a contributor to the acute respiratory distress syndrome (ARDS) in Covid-19, as the major mechanism of severe, often fatal outcome of SARS-CoV-2 infection [3,4,5]. Our data suggest that the latter protein, a truncated, recombinant version of the natural complement inhibitor, factor H (fH) [11,12,13,14,15], may have three independent beneficial actions against CS/CRS; suppression of complement activation and complement-dependent IL-6 production, and, stimulation of IL-10 production, a cytokine with anti-inflammatory properties [16,17,18,19]
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