iC3b‐opsonized apoptotic cells mediate a distinct anti‐inflammatory response and transcriptional NF‐κB‐dependent blockade

Abstract

IsraelIn recent years, it has become apparent that the removal of apoptotic cells by macrophages and DC is not only noninflammatory, but also immune-inhibitory, in most although not all circumstances. Complement may be involved in the uptake of apoptotic cells via direct binding of bridging factors in some physiological circumstances, by opsonization and engagement of the complement receptors. In the current study, we use a complementdependent system of apoptotic cell clearance by human-derived macrophages and DC. Using a luciferase reporter gene and measuring immune response to non-opsonic zymosan, we show that iC3b-apoptotic cells induce NF-jB inhibition in response to zymosan and LPS at the nuclear translocation, transcriptional and post-transcriptional levels, leading to profound inhibition of proinflammatory cytokines. In addition, interaction with iC3b-opsonized apoptotic cells is characterized by macrophage secretion of IL-10 and lack of TGF-b secretion.In conclusion, in cells with iC3b receptors, opsonized apoptotic cells mediate a distinct antiinflammatory response and transcriptional NF-jB-dependent blockage.Key words: Apoptosis . Complement . iC3b . NF-kB IntroductionCells undergoing apoptosis in the human body express cell surface changes that allow recognition by professional phagocytes and/or neighboring cells. Removal of these cells occurs rapidly and without induction of a proinflammatory milieu [1]. In recent years, it has become apparent that the removal of apoptotic cells by macrophages and DC is not only noninflammatory but also immune-inhibitory [2][3][4][5][6][7][8], in most although not all circumstances. Fadok et al. [2] showed that efferocytosis (clearance of apoptotic cells, a terminology suggested by the Henson group) inhibited the production of proinflammatory cytokines such as IL-8 and IL-1b, and induced the secretion of TGF-b, platelet-activating factor, and prostaglandin E2. They further showed and suggested that these factors inhibited a proinflammatory response to LPS and zymosan, by autocrine or paracrine mechanisms, via the secreted factors. Later, Huynh et al. [4] showed that the resolution of acute inflammation is dependent on phosphatidylserine expressed by apoptotic cells, and on TGF-b, secreted most probably by macrophages following engulfment of apoptotic cells expressing phosphatidylserine. further showed that through TGF-b, apoptotic cells simultaneously induce an anti-inflammatory milieu and suppress proinflammatory eicosanoid and NO synthesis in murine macrophages. Hence, the proposed model for à These authors contributed equally to this work. inhibition of a proinflammatory response to LPS and zymosan, as well as the resolution of acute inflammation, is based on ligation of phosphatidylserine expressed on apoptotic cells to the presumed phosphatidylserine receptor, and possibly other receptors. This ligation is expected to result in immediate preformed TGF-b secretion from macrophages, followed by de novo synthesis of TGF-b. Additional mechanisms of inflammatory res...

Complement Component C5 Recruits Neutrophils in the Absence of C3 during Respiratory Infection with Modified Vaccinia Virus Ankara

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A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b

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Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3

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