Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure r...Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic ceils would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis （RA） and systemic lupus erythematosus （SLE）. The IL-12 family of cytokines （IL-12, IL-23, and IL-27） and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells （APCs） and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro- and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein （GC-BP）, through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.展开更多
Phagocytosis of opsonized pathogens by circulating non-adherent neutrophils is an essential step in host defense, which when overwhelmed contributes to sepsis. To investigate the role played by ligation of complement ...Phagocytosis of opsonized pathogens by circulating non-adherent neutrophils is an essential step in host defense, which when overwhelmed contributes to sepsis. To investigate the role played by ligation of complement receptors CR3 and CR4 in non-adherent neutrophils, we designed a novel assay system utilizing dual optical traps, respectively, holding a suspended unactivated cell and presenting a specific ligand-coated bead to the cell surface. We chose anti-CD 18 as an example ligand, mimicking the bacterial opsonizing complement fragment iC3b. Presentation of anti-CD 18-coated beads elicited both pseudopodial protrusion and subsequent phagocytosis. This is in sharp contrast to previously reported responses of adherent neutrophils, which phagocytize opsonized particles without pseudopod formation. We used this same new assay to probe actomyosin pathways in the neutrophil＇s pseudopodial and phagocytic response. Disruption of actin or inhibition of myosin light-chain kinase dose-dependently reduced pseudopod formation and phagocytosis rates. In summary, i） the new dual trap assay can be used to study the responses of suspended neutrophils to a variety of ligands, and ii） in a first application of this technique, we found that local ligation of CR3/4 in unactivated neutrophils in suspension induces pseudopod formation and phagocytosis at that site, and that these events occur via an actomyosindependent pathway.展开更多
Phagocytosis is a fundamental cell biological process exhibited by a wide variety of cell types from single cell organ-isms,which rely on this for feeding,to phagocytes in higher animals,which rely on specialised immu...Phagocytosis is a fundamental cell biological process exhibited by a wide variety of cell types from single cell organ-isms,which rely on this for feeding,to phagocytes in higher animals,which rely on specialised immune cells for com-bating infecting micro-organisms.In the immune system,both macrophages and neutrophils play roles as phagocytes.Neutrophils are often called'professional phagocytes'because of their remarkable capacity for phagocytosis,beingable to internalise microscopic particles(diam 0.5-3 μm)of virtually any surface material.The efficiency and speedof phagocytosis is,however,increased by coating the surface of the particles with opsonins such as antibodies or thecomplement component C3bi(acting on β2 integrin receptors),and C3bi-accelerated phagocytosis by neutrophils is thefirst line of defence by the innate immune system in vivo,operating in advance of the slower production of antibodies.Understanding the mechanism of phagocytosis is,therefore,clearly an important goal.展开更多
文摘Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic ceils would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis （RA） and systemic lupus erythematosus （SLE）. The IL-12 family of cytokines （IL-12, IL-23, and IL-27） and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells （APCs） and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro- and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein （GC-BP）, through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.
文摘Phagocytosis of opsonized pathogens by circulating non-adherent neutrophils is an essential step in host defense, which when overwhelmed contributes to sepsis. To investigate the role played by ligation of complement receptors CR3 and CR4 in non-adherent neutrophils, we designed a novel assay system utilizing dual optical traps, respectively, holding a suspended unactivated cell and presenting a specific ligand-coated bead to the cell surface. We chose anti-CD 18 as an example ligand, mimicking the bacterial opsonizing complement fragment iC3b. Presentation of anti-CD 18-coated beads elicited both pseudopodial protrusion and subsequent phagocytosis. This is in sharp contrast to previously reported responses of adherent neutrophils, which phagocytize opsonized particles without pseudopod formation. We used this same new assay to probe actomyosin pathways in the neutrophil＇s pseudopodial and phagocytic response. Disruption of actin or inhibition of myosin light-chain kinase dose-dependently reduced pseudopod formation and phagocytosis rates. In summary, i） the new dual trap assay can be used to study the responses of suspended neutrophils to a variety of ligands, and ii） in a first application of this technique, we found that local ligation of CR3/4 in unactivated neutrophils in suspension induces pseudopod formation and phagocytosis at that site, and that these events occur via an actomyosindependent pathway.
文摘Phagocytosis is a fundamental cell biological process exhibited by a wide variety of cell types from single cell organ-isms,which rely on this for feeding,to phagocytes in higher animals,which rely on specialised immune cells for com-bating infecting micro-organisms.In the immune system,both macrophages and neutrophils play roles as phagocytes.Neutrophils are often called'professional phagocytes'because of their remarkable capacity for phagocytosis,beingable to internalise microscopic particles(diam 0.5-3 μm)of virtually any surface material.The efficiency and speedof phagocytosis is,however,increased by coating the surface of the particles with opsonins such as antibodies or thecomplement component C3bi(acting on β2 integrin receptors),and C3bi-accelerated phagocytosis by neutrophils is thefirst line of defence by the innate immune system in vivo,operating in advance of the slower production of antibodies.Understanding the mechanism of phagocytosis is,therefore,clearly an important goal.
