Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Abstract

In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model. We also evaluated the effects of adoptive transfer of apoptotic or necrotic cells on the prototypical TH1 and TH2 cytokines IFN-␥ and IL-4, respectively. C57BL6͞J mice had adoptive transfer of apoptotic (irradiated) or necrotic (freeze thaw) splenocytes. Controls received saline. Apoptotic cells greatly increased mortality, whereas necrotic splenocytes markedly improved survival, P < 0.05. The contrasting effects that apoptotic or necrotic cells exerted on survival were mirrored by opposite effects on splenocyte IFN-␥ production with greatly decreased and increased production, respectively. Importantly, either administration of anti-IFN-␥ antibodies or use of IFN-␥ knockout mice prevented the survival benefit occurring with necrotic cells. This study demonstrates that the type of cell death impacts survival in a clinically relevant model and identifies a mechanism for the immune suppression that is a hallmark of sepsis. Necrotic cells (and likely apoptotic cells) exert their effects via modulation of IFN-␥. Sepsis is the leading cause of death in many intensive-care units and currently ranks as the 12th most common cause of death in America (1). Septic patients are severely immune suppressed as typified by their loss of delayed type hypersensitivity, inability to eradicate their primary infection, and a predisposition to develop secondary nosocomial infections (2-6). A feature illustrative of the immune suppression in septic patients is their failure to respond to skin testing with antigens derived from microbes to which previous exposure occurred (positive controls) (2, 7). Animal studies indicate that the immune defect in sepsis may be critical to the pathogenesis and resultant mortality (8-10). Evidence to support this contention is also provided by a recent clinical trial using IFN-␥. Administration of this cytokine, which is a potent macrophage activator and an inducer of the TH1 response, improved survival in patients with sepsis (11).A number of defects in the immune system have been reported in sepsis. These abnormalities include a shift from a proinflammatory TH1 to an antiinflammatory TH2 lymphocyte profile, a loss in cellular MHC II expression, and a profound apoptosisinduced depletion of CD4 T and B cells (5,(11)(12)(13)(14)(15). The sepsis-induced apoptosis of lymphocytes may be particularly important not only because of the extensive lymphocyte loss but also because of a potential immunosuppressive effect of apoptotic cells on the immune system. Recent work has demonstrated that uptake of apoptotic cells by phagocytic cells stimulates immune tolerance by the release of antiinflammatory cytokines and suppression of release of proinflammatory cytokin...

Role of programmed cell death in the immunopathogenesis of sepsis

“…The adoptive transfer of apoptotic cells five days prior to the induction of polymicrobial sepsis markedly reduced septic survival when compared to necrotic cell material or buffer [45]. Mechanistically, this alteration in survival was linked to a decreased production of IFN-γ by splenocytes [45]. In addition, apoptotic cells might alter the immune system not only by modulating inflammation but also by direct influence on the adaptive immunity by providing a variable source of antigen for dendritic cell antigenic processing [46;47].…”

“…These data suggest a mechanism by which the release of antiinflammatory/immunosuppressive mediators might be potentiated during polymicrobial sepsis. The adoptive transfer of apoptotic cells five days prior to the induction of polymicrobial sepsis markedly reduced septic survival when compared to necrotic cell material or buffer [45]. Mechanistically, this alteration in survival was linked to a decreased production of IFN-γ by splenocytes [45].…”

Exploiting death: apoptotic immunity in microbial pathogenesis

“…12 Some microbial pathogens, such as the food-borne bacterium Listeria monocytogenes, 39 trigger host cell death directly. Although several insightful studies have implicated a functionally significant role for the involvement of apoptotic cells in instances of pathogenesis such as these, 40,41 the broader complexity and diversity of apoptotic and apoptoticlike events involved in enhancing microbial pathogenesis has not previously been appreciated fully.…”

“…40,46 Apoptotic cells have been shown to exacerbate the proliferation of Trypanosome parasites, as well. 47 These varied cases illustrate the subversion of apoptosis and apoptotic immunity in serving to enhance microbial pathogenesis.…”

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

“…Other candidate's receptors that may mediate apoptotic cell recognition to suppress immune responses include CD35, avb5 integrin, C1q and the phosphatidylserine receptor [106]. In elegant adoptive transfer experiments using the CLP model, parenteral administration of necrotic cells increased IFN-c levels and decreased mortality, while administration of apoptotic cells had the opposite effect, reducing IFN-c levels and greatly increasing mortality [107]. In these studies, the beneficial effects of necrotic cells were blocked in IFN-c deficient animals or with anti-IFN-c antibodies [107].…”