Indiana University-Purdue University Indianapolis (IUPUI) / Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of
severe skin infections and due to antibiotic resistance there is an intrinsic need to
develop new immunotherapeutic strategies. Skin immune responses to infections
require the cross-talk between phagocytes and structural cells that involves the
secretion of cytokines, chemokines, and lipids. Leukotriene B4 (LTB4) is a
pleiotropic lipid mediator known as a chemoattractant, but is also necessary to
promote antimicrobial activity through B leukotriene receptor 1 (BLT1) signaling.
However, chronic LTB4 production is associated with inflammatory diseases,
including diabetes. People with diabetes are more susceptible to infections. The
determinants by which LTB4/BLT1 promotes protective or detrimental immune
responses in homeostasis and diabetes are unknown. We hypothesize that LTB4
levels determine infection outcome; while LTB4 is necessary for infection control,
excessive LTB4 levels promote overwhelming inflammation that impairs host
defense. Our data show that skin macrophages were necessary for LTB4
production and that LTB4 was vital for neutrophil direction, abscess formation, IL
1β production, and MRSA clearance through reactive oxygen species production.
Importantly, topical LTB4 ointment treatment enhances neutrophil direction,
abscess formation, and bacterial clearance. Conversely, in the setting of diabetes, skin macrophages drove excessive LTB4 production that promoted
overwhelming inflammation, uncontrolled neutrophil recruitment, poor abscess
formation, and lack of bacterial control. Diabetic mice treated with a topical
ointment to inhibit BLT1 dampened inflammation and restored host defense by
improving abscess formation, bacterial clearance, and overall inflammatory
responses in the skin. These data demonstrate the balance of LTB4-induced
inflammation is critical for regulating optimal immune responses during infections.
This work highlights the importance of investigating the role of inflammatory
mediators in the settings of health and disease. Targeting LTB4/BLT1 has
therapeutic potential to regulate inflammation during MRSA skin infection by
enhancing immune responses in settings of vulnerability or decrease
inflammation in diabetes.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/14586 |
| Date | 18 August 2017 |
| Creators | Brandt, Stephanie Lillian |
| Contributors | Serezani, Henrique, Blum, Janice, Kaplan, Mark H., Evans-Molina, Carmella |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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