Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Brandhorst, T. Tristan; Wüthrich, Marcel; Finkel-Jimenez, Bea; Warner, Thomas F.; Klein, Bruce S.

doi:10.4049/jimmunol.173.12.7444

Cited by 53 publications

(42 citation statements)

References 53 publications

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“…This is supported by the influences of GA in models of graft-vs-host disease and inflammatory bowel disease (26). In a recently published study, GA was found to shift the cytokine production of monocytes toward a more anti-inflammatory profile in a MBP-independent fashion (47); ␣ M ␤ 2 is highly expressed on monocytes, and we speculate that GA binding to ␣ M ␤ 2 could be a contributing factor consistent with other observations that ligand binding to this receptor may regulate cytokine production (48).…”

Section: Discussionsupporting

confidence: 70%

Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Stapulionis¹,

Oliveira

Gjelstrup³

et al. 2008

The Journal of Immunology

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Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. We show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin αMβ2 (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with αMβ2, and inhibits the MBP binding to αMβ2. Our study reveals a link between MBP, glatiramer acetate, and the αMβ2 integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the αMβ2 integrin.

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Section: Discussionsupporting

confidence: 70%

Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Stapulionis¹,

Oliveira

Gjelstrup³

et al. 2008

The Journal of Immunology

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“…Therefore, morphological and physiological plasticity allows fungi to rapidly adapt to changing extracellular conditions. Species-specific signaling and morphological features appear to be a direct result of fungal attempts to survive as new microenvironments, and their particular cell stresses, were encountered (Hogan and Klein 1994;Newman et al 1995;Batanghari et al 1998;Sebghati et al 2000;Gow et al 2002;Brandhorst et al 2004;Rappleye et al 2004Rappleye et al , 2007Gantner et al 2005;Nemecek et al 2006;Gauthier and Klein 2008;Nather and Munro 2008;Mora-Montes et al 2011;. The concerted action of morphotype and physiological changes in the context of a particular environment are therefore critical for successful fungal adaptation (Butler et al 2009;O'Connor et al 2010).…”

Section: Resultsmentioning

confidence: 99%

Fungal Morphogenesis

Lin

Alspaugh

Liu

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment. PROPERTIES OF MORPHOGENESIS IN FUNGAL CELLS

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“…However, binding and phagocytosis via the CD11b/CD18 macrophage does not trigger leukotriene release [44] or a respiratory burst [45,46], suggesting noninflammatory functioning. Furthermore, CD11b/ CD18 was shown to be immunosuppressive by downregulation of IL-12 and IFN-g production [47][48][49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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 Ã 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...

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Exploiting Type 3 Complement Receptor for TNF-α Suppression, Immune Evasion, and Progressive Pulmonary Fungal Infection

Cited by 53 publications

References 53 publications

Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

Fungal Morphogenesis

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

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