Granulocyte apoptosis and the control of inflammation

Abstract

We have described a novel pathway available for the clearance of extravasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, a process which leads to their phagocytosis by inflammatory macrophages. By contrast with necrosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would tend to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for macrophage recognition of senescent neutrophils with intact cell membranes which exclude vital dyes and retain their potentially histotoxic granule contents; (ii) the apoptotic neutrophil loses its ability to secrete granule enzymes on deliberate external stimulation; (iii) the macrophage possesses a huge phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil contents; and (iv) the macrophage utilizes a novel phagocytic recognition mechanism which fails to trigger the release of pro-inflammatory macrophage mediators during the phagocytosis of apoptotic neutrophils. Preliminary characterization of the recognition mechanism implicates the integrin alpha v beta 3 (vitronectin receptor) and CD36 (thrombospondin receptor) on the macrophage surface. Macrophage phagocytosis of apoptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifically modulated by external cytokines and intracellular second messenger systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, granulocyte apoptosis, with its potential for modulation by external mediators, is likely to play a key dynamic role in the control of the 'tissue load' of granulocytes at inflamed sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

“…Neutrophils are short-lived, but a central component of their responses to pathogens includes the prolongation of their life span (21). Our work also showed that neutrophil responses to TLR ligands were, in part, mediated by monocytes that commonly contaminate leukocyte preparations (20).…”

Regulation of cytokine production during phagocytosis of apoptotic cells

“…Aberrations in either mechanism are associated with chronic inflammatory conditions and autoimmune disorders [13][14][15]. Uptake of apoptotic cells by phagocytes is thought to suppress autoimmune responses through the release of anti-inflammatory cytokines IL-10, TGF-β, platelet activating factor (PAF), and prostaglandin E 2 (PGE 2 ), and inhibition of proinflammatory cytokines TNF-α, GM-CSF, IL-12, IL-1β, and IL-18 [16][17][18].…”

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

“…Aberrations in either mechanism are associated with chronic inflammatory conditions and autoimmune disorders. [40][41][42] Uptake of apoptotic cells by phagocytes is thought to suppress autoimmune responses through the release of anti-inflammatory cytokines IL-10, transforming growth factor-b, platelet-activating factor and prostaglandin E 2 , and inhibition of proinflammatory cytokines TNF-a, granulocyte-macrophage colony-stimulating factor, IL-12, IL-1b and IL-18. [43][44][45] Our group recently has shown that during phagocytosis by macrophages, apoptotic cell-derived signals trigger dephosphorylation and activation of a novel nuclear zinc finger-like protein, named GC-binding protein, which targets a specific site in the IL-12 p35 gene promoter, preventing its transcription.…”