Macrophage-derived LTB4 promotes abscess formation and clearance of Staphylococcus aureus skin infection in mice.

Stephanie L Brandt,Lloyd Miller,Seth Winfree,C Henrique Serezani,Brian P Mccarthy,Soujuan Wang,Nathan Klopfenstein,Paul R Territo,Alice Prince

doi:10.1371/journal.ppat.1007244

Abstract

The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.

Highlights

Staphylococcus aureus is a significant cause of severe skin and soft tissue infections that can progress to life-threatening infections, such as osteomyelitis or sepsis, if left untreated [1,2,3]
We unveiled the role of skin macrophages in the generation of the lipid mediator leukotriene B4 (LTB4) that culminates in optimal chemokine/cytokine production, abscess formation, and bacterial clearance
An ointment containing LTB4 and antibiotics improved skin host defense and abscess formation and enhanced bacterial clearance. These results suggest that LTB4 could be used locally as an immunotherapeutic agent to strengthen/restore innate immune host activation during Methicillin-resistant Staphylococcus aureus (MRSA) skin infections

Summary

Introduction

Staphylococcus aureus is a significant cause of severe skin and soft tissue infections that can progress to life-threatening infections, such as osteomyelitis or sepsis, if left untreated [1,2,3]. The inflammatory response to S. aureus infection is orchestrated by the interaction among structural cells of the skin and both resident and recruited phagocytes [4]. Keratinocytes and resident immune cells produce antimicrobials to clear the pathogens and generate cytokines, chemokines, and lipid mediators to further activate dermal macrophages and promote neutrophil recruitment to the site of infection [4]. We and others have shown that the lipid mediator leukotriene B4 (LTB4) directly enhances neutrophil migration to inflammatory sites and amplifies in vitro pathogen recognition and antimicrobial effector functions [8]. Yamamoto et al [15] have shown that treatment of mice with LTB4 increased the clearance of MRSA peritoneal infection, but the cellular players and molecular mechanisms involved in in vivo host defense are unknown

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