Complement-Induced Impairment of Innate Immunity During Sepsis

Huber‐Lang, Markus; Younkin, Ellen M.; Sarma, J. Vidya; McGuire, Stephanie; Lu, Kristina T.; Guo, Ruocheng; Padgaonkar, Vaishalee A.; Curnutte, John T.; Erickson, Rich; Ward, Peter A.

doi:10.4049/jimmunol.169.6.3223

Cited by 170 publications

(169 citation statements)

References 47 publications

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“…Previous in vitro experiments suggested that the binding of C5a could lead to the reduced surface expression of C5aR, which rendering cells resistant to subsequent challenges with C5a. 16 Here, we showed that C5a rapidly induced the internalization of C5aR and C5L2 within human neutrophils. Interestingly, the plasma concentration of C5a was not significantly changed in patients with sepsis in our study (data not shown), which most likely reflects increased C5a consumption during the inflammatory response.…”

Section: Discussionmentioning

confidence: 74%

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

Lin

Bao

et al. 2015

Cell Mol Immunol

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Section: Discussionmentioning

confidence: 74%

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

Lin

Bao

et al. 2015

Cell Mol Immunol

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“…C5aR is widely expressed on myeloid cells, but whether it is expressed on T cells, especially on gd T cells, was not clear [21][22][23]. We assumed that the mechanism of C5a modulation of gd T cells during sepsis might be indirect.…”

Section: Discussionmentioning

confidence: 99%

“…Most importantly, gd T cells derived from the C5a blockade group lost their pathogenic role in adoptive transfer. These results suggest an intimate link between C5a, gd T cells and IL-17.C5aR is widely expressed on myeloid cells, but whether it is expressed on T cells, especially on gd T cells, was not clear [21][22][23]. We assumed that the mechanism of C5a modulation of gd T cells during sepsis might be indirect.…”

mentioning

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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“…Although these results associate uninhibited complement amplification with increased migration of ME180 cervical cancer cells, a direct influence of these complement proteins on tumor chemotaxis remains unverified. In combination with data demonstrating that excessive C5a disrupts neutrophil chemotaxis (155), it would seem that complementmediated cellular migration is highly dependent on a variety of local immunologic cues.…”

Section: Complement and Immunosurveillancementioning

confidence: 99%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

229

249

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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Complement-Induced Impairment of Innate Immunity During Sepsis

Cited by 170 publications

References 47 publications

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

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

Cancer and the Complement Cascade

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