Bacterial Lipoprotein Delays Apoptosis in Human Neutrophils through Inhibition of Caspase-3 Activity: Regulatory Roles for CD14 and TLR-2

Department of Academic Surgery, National University of Ireland, Cork University Hospital.
The Journal of Immunology (Impact Factor: 4.92). 11/2004; 173(8):5229-37. DOI: 10.4049/jimmunol.180.1.664
Source: PubMed


The human sepsis syndrome resulting from bacterial infection continues to account for a significant proportion of hospital mortality. Neutralizing strategies aimed at individual bacterial wall products (such as LPS) have enjoyed limited success in this arena. Bacterial lipoprotein (BLP) is a major constituent of the wall of diverse bacterial forms and profoundly influences cellular function in vivo and in vitro, and has been implicated in the etiology of human sepsis. Delayed polymorphonuclear cell (PMN) apoptosis is a characteristic feature of human sepsis arising from Gram-negative or Gram-positive bacterial infection. Bacterial wall product ligation and subsequent receptor-mediated events upstream of caspase inhibition in neutrophils remain incompletely understood. BLP has been shown to exert its cellular effects primarily through TLR-2, and it is now widely accepted that lateral associations with the TLRs represent the means by which CD14 communicates intracellular messages. In this study, we demonstrate that BLP inhibits neutrophil mitochondrial membrane depolarization with a subsequent reduction in caspase-3 processing, ultimately leading to a significant delay in PMN apoptosis. Pretreatment of PMNs with an anti-TLR-2 mAb or anti-CD14 mAb prevented BLP from delaying PMN apoptosis to such a marked degree. Combination blockade using both mAbs completely prevented the effects of BLP (in 1 and 10 ng/ml concentrations) on PMN apoptosis. At higher concentrations of BLP, the antiapoptotic effects were observed, but were not as pronounced. Our findings therefore provide the first evidence of a crucial role for both CD14 and TLR-2 in delayed PMN apoptosis arising from bacterial infection.

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    • "Its function in these cells is even more obscure. The membrane bound form of CD14 has been related to apoptosis in different ways; it was suggested to act as a tethering receptor for apoptotic cells on the surface of phagocytes, to facilitate removal of apoptotic cells, and also as a surface membrane molecule possibly associated with resistance from apoptosis of monocytes, neutrophils and, as demonstrated recently, of enterocytes, challenged with LPS (Gregory 2000; Devitt et al. 1998; Heidenreich et al. 1997; Heidenreich 1999; Yu et al. 2006; Devitt et al. 2004; Power et al. 2004). Whether soluble CD14 has additional functions or activities related to apoptosis is less established. "
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    • "Sohn et al. (2007) have reported that bovine CD14 + PMN bound to LPS resulted in a downregulation of apoptosis. Moreover, CD14 expression delayed PMN apoptosis triggered by bacterial lipoproteins and lipoteichoic acid (Lotz et al., 2004; Power et al., 2004). "
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    • "Neutrophil accumulation at the inflammatory foci and survival have been implicated in the pathology of other inflammatory diseases such as arthritis, meningitis and peritonitis [27] [29]. As previously observed for other bacterial lipoproteins [16], B. abortus lipoproteins mediated apoptotic delay. Hence, by delaying apoptosis B. abortus lipoproteins may further contribute to the pathogenesis of brucellosis, over-riding apoptotic neutrophils removal by phagocytic cells and limiting inflammation resolution. "
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