Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis

Area of Science:

• Immunology
• Biochemistry
• Microbiology

Background:

• Neutrophils utilize the myeloperoxidase (MPO) system to generate hypochlorous acid (HOCl) from hydrogen peroxide and chloride.
• HOCl is a potent bactericidal oxidant effective in vitro.
• The in vivo role of MPO in host defense against sepsis requires further elucidation.

Purpose of the Study:

• To investigate the protective role of MPO in a mouse model of polymicrobial sepsis.
• To identify MPO-derived products in inflammatory fluid during sepsis.
• To determine if MPO utilizes halides other than chloride in vivo.

Main Methods:

• A mouse model of polymicrobial sepsis was employed.
• Myeloperoxidase-deficient and wild-type mice were compared.
• Mass spectrometric analysis of peritoneal inflammatory fluid was performed.
• In vitro experiments assessed MPO's bactericidal activity in the presence of bromide.

Main Results:

• Mice deficient in MPO exhibited increased mortality during sepsis compared to wild-type mice.
• Elevated levels of 3-chlorotyrosine, an MPO product, were detected in septic wild-type mice but not in MPO-deficient mice.
• Surprisingly, 3-bromotyrosine was also elevated in septic wild-type mice and reduced in MPO-deficient mice.
• Physiologic bromide concentrations modulated MPO's in vitro bactericidal activity.

Conclusions:

• Myeloperoxidase plays a crucial protective role against sepsis in vivo by generating halogenating species.
• MPO can utilize bromide, in addition to chloride, to produce oxidants in vivo, despite lower extracellular bromide concentrations.
• Bromide may represent a previously unrecognized component of the MPO-mediated host defense system against bacterial pathogens.