Prostaglandin E2–Induced Changes in Alveolar Macrophage Scavenger Receptor Profiles Differentially Alter Phagocytosis of Pseudomonas aeruginosa and Staphylococcus aureus Post–Bone Marrow Transplant

Abstract

The effectiveness of hematopoietic stem cell transplantation as a therapy for malignant and nonmalignant conditions is complicated by pulmonary infections. Using our syngeneic bone marrow transplant (BMT) mouse model, BMT mice with a reconstituted hematopoietic system displayed increased susceptibility to Pseudomonas aeruginosa and Staphylococcus aureus. BMT alveolar macrophages (AMs) exhibited a defect in P. aeruginosa phagocytosis while S. aureus uptake was surprisingly enhanced. We hypothesized that the difference in phagocytosis was due to an altered scavenger receptor (SR) profile. Interestingly, MARCO expression was decreased while SR-AI/II was increased. To understand how these dysregulated SR profiles might affect macrophage function, CHO cells were transfected with SR-AI/II and phagocytosis assays revealed that SR-AI/II was important for S. aureus uptake but not P. aeruginosa. Conversely, AMs treated in vitro with soluble MARCO exhibited similar defects in P. aeruginosa internalization as BMT AMs. The 3'UTR of SR-AI contains a putative target region for miR-155 and miR-155 expression is decreased post-BMT. Anti-miR-155-transfected AMs exhibited an increase in SR-AI/II expression and S. aureus phagocytosis. Elevated PGE2 has been implicated in driving an impaired innate immune response post-BMT. In vitro treatment of AMs with PGE2 increased SR-AI/II, and decreased MARCO and miR-155. Despite a difference in phagocytic ability, BMT AMs harbor a killing defect to both P. aeruginosa and S. aureus. Thus, our data suggest that PGE2-driven alterations in scavenger receptor and miR-155 expression account for the differential phagocytosis of P. aeruginosa and S. aureus but impaired killing ultimately confers increased susceptibility to pulmonary infection.

Transforming growth factor-β induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation

“…Killing of phagocytized S. aureus was measured in AMs from BMT mice and untransplanted control mice. BMT AMs exhibited impaired S. aureus killing compared with control AMs, supporting a previous study whereby BMT mice exhibited higher susceptibility to S. aureus in vivo, which correlated to impaired killing by BMT AMs (18). However, reconstituting the alveolar compartment with donor AMs insensitive to TGF-␤ (CD11c dnR BMT) rescued this killing defect (Fig.…”

“…Interestingly, observations made in patients undergoing HSCT note impaired function in the innate immune compartment (i.e., AMs and neutrophils) (11,59,63). Using a murine model of BMT to understand the correlation between these defective innate immune cells and the increased susceptibility of these patients, we previously published that BMT AMs are unable to phagocytize P. aeruginosa and kill engulfed P. aeruginosa or S. aureus well (5,13,18,42). These defects were primarily mediated by the overproduction of PGE 2 , as demonstrated by rescue of P. aeruginosa phagocytosis and killing of both P. aeruginosa and S. aureus in BMT AMs by inhibition of PGE 2 or the COX-2 pathway in vitro (5).…”

“…This model sheds light on the underlying effects of transplantation on immune cell function independent of immunosuppressive therapy or development of graft-vs.-host disease (28). Using this model, we previously reported that BMT mice were more susceptible to Gram-negative (Pseudomonas aeruginosa, P. aeruginosa) and Gram-positive (Staphylococcus aureus, S. aureus) pneumonia (18,42). This increased susceptibility was at least partially attributed to functionally defective AMs (5-7, 14, 18, 19, 26 -28).…”

“…Similarly to human HSCT AMs, murine AMs after BMT exhibit impaired phagocytosis and bacterial killing (14,19,59). Specifically, phagocytosis of P. aeruginosa is diminished because of reduced levels of the macrophage receptor with collagenous structure (MARCO) on AMs after BMT, whereas phagocytosis of S. aureus is actually increased because of elevations of scavenger receptor A (18). Despite these differences in phagocytosis, however, BMT AMs display defects in intracellular killing of both of these pathogens (18).…”

“…Specifically, phagocytosis of P. aeruginosa is diminished because of reduced levels of the macrophage receptor with collagenous structure (MARCO) on AMs after BMT, whereas phagocytosis of S. aureus is actually increased because of elevations of scavenger receptor A (18). Despite these differences in phagocytosis, however, BMT AMs display defects in intracellular killing of both of these pathogens (18). These defects were attributed to overexpression of cyclooxygenase (COX)-2 and increased production of its downstream effector, prostaglandin E 2 (PGE 2 ).…”