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Unresolved experimental Lyme arthritis in C3H 5-lipoxygenase (5-LOX)−/−mice is associated with impaired macrophage phagocytosis of Borrelia burgdorferi. In the present study, we further investigated the effects of the 5-LOX metabolite, leukotriene (LT)B4on phagocytosis of B. burgdorferi. Bone marrow-derived macrophages (BMDMs) from 5-LOX−/−mice were defective in the uptake and killing of B. burgdorferifrom the earliest stages of spirochete internalization. BMDMs from mice deficient for the LTB4high-affinity receptor (BLT1−/−) were also unable to efficiently phagocytose B. burgdorferi. Addition of exogenous LTB4augmented the phagocytic capability of BMDMs from both 5-LOX−/−and BLT1−/−mice, suggesting that the low-affinity LTB4receptor, BLT2, might be involved. Blocking BLT2 activity with the specific antagonist, LY255283, inhibited phagocytosis in LTB4-stimulated BLT1−/−BMDMs, demonstrating a role for BLT2. However, the lack of a phagocytic defect in BLT2−/−BMDMs suggested that this was a compensatory effect. In contrast, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, a natural BLT2-specific high-affinity ligand, and resolvin E1, a BLT1 agonist, were both unable to boost phagocytosis in BMDMs from either 5-LOX−/−or BLT1−/−mice, suggesting a specific role for LTB4in mediating phagocytosis in murine macrophages. This study demonstrates that LTB4promotes macrophage phagocytosis of bacteria via BLT1, and that BLT2 can fulfill this role in the absence of BLT1.

ABSTRACTInfection of C3H mice with Borrelia burgdorferi, the causative agent of Lyme disease, reliably produces an infectious arthritis and carditis that peak around 3 weeks postinfection and then spontaneously resolve. Macrophage polarization has been suggested to drive inflammation, the clearance of bacteria, and tissue repair and resolution in a variety of infectious disease models. During Lyme disease it is clear that macrophages are capable of clearing Borreliaspirochetes and exhausted neutrophils; however, the role of macrophage phenotype in disease development or resolution has not been studied. Using classical (NOS2) and alternative (CD206) macrophage subset-specific markers, we determined the phenotype of F4/80+macrophages within the joints and heart throughout the infection time course. Within the joint, CD206+macrophages dominated throughout the course of infection, and NOS2+macrophage numbers became elevated only during the peak of inflammation. We also found dual NOS2+CD206+macrophages which increased during resolution. In contrast to findings for the ankle joints, numbers of NOS2+and CD206+macrophages in the heart were similar at the peak of inflammation. 5-Lipoxygenase-deficient (5-LOX−/−) mice, which display a failure of Lyme arthritis resolution, recruited fewer F4/80+cells to the infected joints and heart, but macrophage subset populations were unchanged. These results highlight differences in the inflammatory infiltrates during Lyme arthritis and carditis and demonstrate the coexistence of multiple macrophage subsets within a single inflammatory site.

Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing bronchopneumonia involving focal bacterial growth, neutrophilic congestion, and alveolar necrosis. Within a short time after inhalation of Y. pestis, inflammatory cytokines are expressed via the Toll/interleukin-1 (IL-1) adaptor myeloid differentiation primary response 88 (MyD88), which facilitates the primary lung infection.

Pneumonic plague, caused by the Gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection. Consequently, primary pneumonic plague is a multiorgan disease involving sepsis and necrosis of immune tissues and the liver, as well as bronchopneumonia and rampant bacterial growth.

Yersinia pestiscauses bubonic, pneumonic, and septicemic plague. Although no longer responsible for pandemic outbreaks, pneumonic plague continues to be a challenge for medical treatment and has been classified as a reemerging disease in some parts of the world.

ABSTRACTYersinia pestiscauses bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans. Plague develops as a consequence of bacterial neutralization of the host's innate immune response, which permits uncontrolled growth and causes the systemic hyperactivation of the inflammatory response. We previously found that host type I interferon (IFN) signaling is induced during Y. pestisinfection and contributes to neutrophil depletion and disease. In this work, we show that type I IFN expression is derived from the recognition of intracellular Y. pestisby host Toll-like receptor 7 (TLR7). Type I IFN expression proceeded independent of myeloid differentiation factor 88 (MyD88), which is the only known signaling adaptor for TLR7, suggesting that a noncanonical mechanism occurs in Y. pestis-infected macrophages. In the murine plague model, TLR7 was a significant contributor to the expression of serum IFN-β, whereas MyD88 was not. Furthermore, like the type I IFN response, TLR7 contributed to the lethality of septicemic plague and was associated with the suppression of neutrophilic inflammation. In contrast, TLR7 was important for defense against disease in the lungs. Together, these data demonstrate that an atypical TLR7 signaling pathway contributes to type I IFN expression during Y. pestisinfection and suggest that the TLR7-driven type I IFN response plays an important role in determining the outcome of plague.