Global changes in gene expression by human polymorphonuclear leukocytes during receptor-mediated phagocytosis: Cell fate is regulated at the level of gene expression

Abstract

Phagocytes are a critical component of the innate immune response in humans and eliminate invading microorganisms through a process known as phagocytosis. Two distinct receptor-linked phagocytic pathways, one with Ab receptors (FcRs; FcR, Fc receptor) and the other complement receptors (CRs), mediate binding and ingestion of pathogens by human polymorphonuclear leukocytes (PMNs). Although progress has been made toward defining complex signal transduction processes that underlie phagocytosis in each pathway, very little is known about gene regulation during or after phagocytosis. Therefore, we used human oligonucleotide microarrays to identify changes in expression of 12,561 genes accompanying FcR-and CR-mediated phagocytosis. Eighty-four percent of 279 differentially expressed genes were induced or repressed 90 min after ingestion of Ab-and͞or complementopsonized particles. Unexpectedly, more than 30 of these genes encoded proteins involved in at least three distinct apoptotic pathways. Ninety-four differentially expressed cell fate-related genes were identified between 180 and 360 min after phagocytosis and most were induced or repressed by PMNs activated through both receptors simultaneously. By using flow cytometry, we found that FcR-and CR-mediated phagocytosis each promoted programmed cell death in human PMNs; however, phagocytosis mediated by the combination of FcRs and CRs induced apoptosis earlier than that by either receptor alone. Our results reveal distinct patterns of receptor-mediated gene expression that define complex inducible apoptotic pathways in activated PMNs. Most significantly, we discovered that programmed cell death is regulated at the level of gene expression. Thus, we hypothesize that gene regulation in PMNs facilitates resolution of inflammatory responses.

Phagocytosis induces superoxide formation and apoptosis in macrophages

“…Using oligonucleotide microarrays and FACS analysis, it was confirmed that apoptosis can be induced during phagocytosis (Kobayashi et al, 2002).…”

Critical role for complement receptor 3 (CD11b/CD18), but not for Fc receptors, in killing of Streptococcus pyogenes by neutrophils in human immune serum

“…In general, activation of the NADPH oxidase system is believed to require stimulation of FcR, and in particular of CD32 [10,24], even if immobilized on surfaces or fed with particles that cannot be ingested, respiratory burst in neutrophils can be induced through CD11b/CD18 [25]. Consistent with the observation that killing of M3 streptococci was dependent on iC3b-CD11b/CD18 binding, we found that respiratory burst induced by the streptococci in immune serum was reduced by sCR1 and anti-CD11b, but not by anti-CD32 (Fig.…”

Constitutive neutrophil apoptosis: Mechanisms and regulation

“…This death mechanism also requires NADPH oxidase-derived ROS produced during phagocytosis and the subsequent activation of caspase-8 and -3 [27,35]. Recently, Kobayashi et al proposed that phagocytosis-elicited neutrophil death is regulated at the level of gene expression, since a variety of genes encoding key effectors of apoptosis are upregulated during this process [106,107].…”