Inactivation of Human β-Defensins 2 and 3 by Elastolytic Cathepsins

Abstract

β-Defensins are antimicrobial peptides that contribute to the innate immune responses of eukaryotes. At least three defensins, human β-defensins 1, 2, and 3 (HBD-1, -2, and -3), are produced by epithelial cells lining the respiratory tract and are active toward Gram-positive (HBD-3) and Gram-negative (HBD-1, -2, and -3) bacteria. It has been postulated that the antimicrobial activity of defensins is compromised by changes in airway surface liquid composition in lungs of patients with cystic fibrosis (CF), therefore contributing to the bacterial colonization of the lung by Pseudomonas and other bacteria in CF. In this report we demonstrate that HBD-2 and HBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S. In addition, we show that all three cathepsins are present and active in CF bronchoalveolar lavage. Incubation of HBD-2 and -3 with CF bronchoalveolar lavage leads to their degradation, which can be completely (HBD-2) or partially (HBD-3) inhibited by a cathepsin inhibitor. These results suggest that β-defensins are susceptible to degradation and inactivation by host proteases, which may be important in the regulation of β-defensin activity. In chronic lung diseases associated with infection, overexpression of cathepsins may lead to increased degradation of HBD-2 and -3, thereby favoring bacterial infection and colonization.

Identification of hBD-3 in respiratory tract and serum: the increase in pneumonia

“…Synthetic hBD-3 exhibits a broad-spectrum antimicrobial activity against both gram-positive and gram-negative bacteria [2,3], while hBD-1 and hBD-2 are more potent against gram-negative bacteria [1,2]. Recently, host protease cathepsins were shown to degrade defensins; thus, overexpression of cathepsins may produce an environment favouring bacterial infection and colonisation during chronic pulmonary infectious diseases [20]. All defensin molecules are strongly cationic, facilitating their interactions with bacteria and allowing the formation of channels within the negatively charged cytoplasmic membranes [21].…”

Targeting neutrophil elastase in cystic fibrosis

“…However, whereas elafin is inactivated by NE in CF ELF [17], SLPI is relatively immune to the direct proteolytic effects of NE but is readily proteolysed by cysteinyl cathepsins [69] and metalloproteases both of which are upregulated by NE [23]. Cysteinyl proteases also cleave and inactivate defensins [70] and lactoferrin, two locally produced anti-microbials with direct relevance to CF as defensins are key mediators of Pseudomonas killing and lactoferrin has a major role in inhibiting biofilm formation [71].…”

Enterohemorrhagic and enteropathogenic Escherichia coli evolved different strategies to resist antimicrobial peptides

“…For example, the host cathepsins B, L and S were shown to inactivate hBD-2 and hBD-3. 24 In addition, the cysteine proteases, known as gingipains, produced by Porphyromonas gingivalis degrade hBD-3. 25 The Proteus mirabilis ZapA and Burkholderia cenocepacia ZmpB zinc-dependent metalloproteases degraded hBD-1.…”