Proteases produced by activated neutrophils release soluble CD23 fragments endowed with proinflammatory effects

Abstract

Polymorphonuclear neutrophils (PMNs) are the major source of proteolytic activities involved mainly in tissue injuries observed in chronic inflammatory disorders. High levels of soluble forms of CD23 (the low-affinity receptor for IgE) were found in biological fluids from these patients, and recent reports focused on a CD23-mediated regulation of inflammatory response. In this context, we show here that co-culture of activated PMN with CD23+ B cells resulted in a drastic release of soluble CD23 fragments from the cell surface. This cleavage was inhibited by serine proteases inhibitors, including a1-antitrypsin. We next demonstrated that purified human leukocyte elastase or cathepsin G efficiently cleaved membrane CD23 on B cells with a high specificity. Soluble fragments released by serine proteases-mediated CD23 proteolysis stimulated resting monocytes to produce oxidative burst and proinflammatory cytokine without any co-stimulatory signal. This work strongly supports the idea that the capacity of PMN-derived proteases to release soluble forms of CD23 participates in the inflammatory process mediated by these cells.

Polymorphism R62W results in resistance of CD23 to enzymatic cleavage in cultured cells

“…They have been reported to cleave membrane CD23 and account for the release of soluble CD23 fragments. 23 Thus, we compared their capacity to cleave membrane CD23 in transiently transfected Cos-7 cells among different genotypes. At 48 h after transfection, Cos-7 cells transfected with CC, CT and TT as well as EBV transformed B cells were cultured in the presence or absence of HLE (200 mg/ml, 1 h) and cathepsin G (25 mg/ ml, 1 h).…”

“…Numerous endogenous enzymes such as HLE, cathespin G and perhaps others could be produced from mononuclear cells and could affect this process. 23 Therefore, the cSNP R62W may contribute to immune mediated dysfunction in allergic reactions. The ADAM (a disintegrin and metalloproteinase) gene family is a subgroup of the zinc-dependent metalloproteinase superfamily, which mediates extracellular matrix remodeling during discrete physiological processes.…”

Neutrophil serine proteases fine-tune the inflammatory response

“…The soluble IL-6 receptor subunits retain ligand-binding capacity and therefore may influence cellular responsiveness to IL-6. In addition, CG and NE can release soluble CD23 fragments that stimulate monocytes to produce oxidative burst and pro-inflammatory cytokines without any co-stimulatory signals (Brignone et al, 2001). In summary, these studies suggest that neutrophil serine proteases have the potential to activate and shed many receptors.…”

Immuno-evasive tactics by schistosomes identify an effective allergy preventative

“…Schistosomes use a plethora of proteases during parasitism, including cysteine proteases, elastases, calpain, thioredoxin and peroxidases, some of which cleave IgE (43–46). To determine if a schistosomal protease might cleave CD23, we incubated purified, IL-4-treated B cells with schistosome antigens in the presence of inhibitors to classes of proteases previously shown to cleave CD23 (24, 39, 42). Our results demonstrate that, whereas inhibitors of cathepsin L and capthesin B did not change the level of sCD23 generated in the presence of schistosome antigens, leupeptin inhibited the accumulation of total sCD23 in cell supernatants (Fig.…”

“…Smaller sCD23 fragments, 17- and 25- kDa, bind IgE and CD21 and are released from the cleavage of larger soluble molecules by several host and microbial proteases. For example, neutrophils secrete an elastase, which cleaves the 37kDa fragment into the 25kDa sCD23 fragment, which can be visualized in the serum (24). These smaller fragments lack the stalk region and generally exist as monomers.…”