The Role of Programmed Cell Death (Apoptosis) in Thymic Involution Following Sepsis

Barke, Roderick A.; Roy, Sabita; Chapin, Rebecca B.; Charboneau, Richard

doi:10.1001/archsurg.1994.01420360046005

Cited by 34 publications

(16 citation statements)

References 17 publications

(4 reference statements)

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“…Simultaneously, humoral defense mechanisms such as the complement system are activated, resulting in production of proinflammatory mediators, including C3a and C5a, which are powerful pathogenic mediators. Published data provide compelling evidence for the beneficial effects of blocking either C5a or C5aR (CD 88 ) in experimental sepsis, which is associated with attenuated coagulopathy, preservation of thymic function, rescue of lymphocytes from apoptosis and reduced levels of bacteremia [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Xu¹,

Wang²,

Han³

et al. 2010

Eur J Immunol

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Complement 5a (C5a) and are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by cd T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by cd T cells. Dendritic cells (DC) were found to act as a ''bridge'' between C5a and cd T cells in a mechanism involving IL-6 and transforming growth factor b (TGF-b). These results imply that C5a affects the crosstalk between DC and cd T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17.Key words: Complement system . gd T cells . Immunopathology IntroductionSepsis is a life-threatening medical condition caused by various microorganisms entering the human bloodstream and triggering an uncontrolled inflammatory reaction. In light of the multifactorial pathogenesis of sepsis, extensive work has been done to characterize the numerous agents and mediators that are involved in sepsis. In spite of extensive research efforts over the last 20 years, sepsis remains the leading cause of death in intensive care units [1,2]. Specific therapies are generally unavailable because pathogenic mechanisms are still unclear.There is abundant evidence that complement activation, production of cytokines and other inflammatory responses occur in sepsis [3]. It is generally accepted that the complement activation product complement 5a (C5a) plays an important inflammatory role in rodents following cecal ligation and puncture (CLP) [4]. C5a exerts its effects through the high-affinity C5a receptor (C5aR) and C5L2. C5L2, a putative ''default'' receptor, has been suggested to play important role in balancing the biological effect of C5a. For example, recent data showed that both C5aR and C5l2 cooperatively play functional parts in the setting of sepsis [5]. It has been shown that blockade of C5a or its receptor (C5aR) can inhibit the development of CLP and is associated with decreased levels of bacteria, preservation of innate immune functions of blood neutrophils, reduced thymocyte apoptosis and greatly improved survival rates [6,7].IL-17 (also known as IL-17A) is a proinflammatory cytokine produced by a variety of cells including CD4 1 Th17 cells, CD8 1 T cells, neutrophils and NK cells [8]. Recent reports also suggested that gd T cells are a major source of . Although it has been demonstrated that IL-17 plays an important role in Ã These authors contributed equally to this paper. Understanding crosstalk between critical pathogenic factors may be very important for designing treatments for sepsis. Here, we studied the crosstalk between two critical pathogenic factors, C5a and IL-17. Our results show that C5a acted on DC, which subsequently induced gd T cells to secrete IL-17. ResultsC5a induced IL-17 in CLP-induce...

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Section: Discussionmentioning

confidence: 99%

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Xu¹,

Wang²,

Han³

et al. 2010

Eur J Immunol

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“…A number of physiological and infectious situations induce thymus involution by as yet unidentified mechanisms [3][4][5][6][7][8][9][10]. In pregnancy, thymus atrophy and the reduction in the release of lymphoid precursor cells by the bone marrow are considered part of a complex adaptative system to avoid fetus rejection [4,30].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the primary importance of the thymus in the development of a mature immune system and in the control of autoimmune diseases, a number of physiological situations induce thymus involution, such as aging [3] and pregnancy [4]. Moreover, sepsis [5], murine infection with some viruses [6][7][8], and Schistosoma mansoni [9] also induce thymic atrophy. During the acute phase of Trypanosoma cruzi infection, the etiologic agent of Chagas' disease, thymic atrophy is also observed, both in humans and in mice.…”

Section: Introductionmentioning

confidence: 99%

Extracellular ATP induces cell death in CD4+/CD8+ double-positive thymocytes in mice infected with Trypanosoma cruzi

Mantuano-Barradas

Henriques-Pons

Araújo-Jorge

et al. 2003

Microbes and Infection

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“…Extensive lymphocyte apoptosis accompanied by depletion of lymphocytes in white pulp of the spleen and development of lymphocytopenia has been found in most cases of humans with sepsis (5). Atrophy of the thymus associated with thymocyte apoptosis has been observed in a model of Gram-negative or -positive sepsis, as well as in CLP-induced sepsis in rodents (6)(7)(8). Tcell suppression and a decrease in total T-lymphocyte numbers are characteristic symptoms in MOFS (2).…”

Section: Introductionmentioning

confidence: 99%

Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis

Guo¹,

Huber‐Lang²,

Wang³

et al. 2000

J. Clin. Invest.

147

114

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Multiorgan apoptosis occurs during sepsis. Following cecal ligation and puncture (CLP) in rats, thymocytes underwent apoptosis in a time-dependent manner. C5a blockade dramatically reduced thymocyte apoptosis as measured by thymic weight, binding of annexin V to thymocytes, and laddering of thymocyte DNA. When C5a was generated in vivo by infusion of purified cobra venom factor (CVF), thymocyte apoptosis was significantly increased. Similar results were found when CVF was injected in vivo during the early stages of CLP. In animals 12 hours after induction of CLP, there was an increase in the activities of caspase-3, -6, and -9, but not caspase-1 and -8. Cytosolic cytochrome c levels increased by twofold, whereas mitochondrial levels showed a 50% decrease. Western blot analysis revealed that the content of Bcl-X L (but not of Bcl-2, BAX, Bad, and Bim) significantly decreased in thymocytes after CLP. C5a blockade in the sepsis model almost completely inhibited caspase-3, -6, and -9 activation, significantly preserved cytochrome c in the mitochondrial fraction, and restored Bcl-X L expression. These data suggest that systemic activation of complement induces C5a-dependent apoptosis of thymocytes and that the blockade of C5a during sepsis rescues thymocytes from apoptosis.

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The Role of Programmed Cell Death (Apoptosis) in Thymic Involution Following Sepsis

Abstract: Thymic involution following peritoneal sepsis is associated with increased thymocyte programmed cell death. Thymocyte apoptosis induced by sepsis may be the result, in part, of inhibition of IL-2 gene expression.

Cited by 34 publications

References 17 publications

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Extracellular ATP induces cell death in CD4+/CD8+ double-positive thymocytes in mice infected with Trypanosoma cruzi

Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis

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