Impaired Pulmonary Host Defense Against Pseudomonas aeruginosa Following Bone Marrow Transplantation.

Abstract

Hematopoietic stem cell transplant (HSCT) patients are especially susceptible to lung infections, despite immune reconstitution. In a mouse model of syngeneic bone marrow transplantation (BMT), we previously reported that prostaglandin E2 (PGE2) is overproduced in lungs of BMT mice, significantly impairing pulmonary host defense against Pseudomonas aeruginosa. This impairment in pulmonary host defense post-BMT is also marked by diminished alveolar macrophage (AM) function. These data were generated using total body irradiation (TBI) as a means to ablate host bone marrow. Therefore, we wanted to determine whether the use of clinically relevant chemotherapy regimens to ablate host bone marrow would result in similar findings. We compared donor-cell reconstitution, pulmonary host defense, and PGE2 production among control and BMT mice conditioned with either TBI or chemotherapy. Dual chemotherapy conditioned mice had a lower frequency of donor-derived cells compared to TBI; however, both groups displayed similar impairment in AM host defense and bacterial clearance following P. aeruginosa pneumonia. Furthermore, impairment in AM host defense was directly related to overproduction of PGE2 in both groups. These data suggest that compared to TBI, use of chemotherapy conditioning results in similar PGE2-mediated suppression of pulmonary host defense in BMT mice, despite reduced efficiency of donor-cell reconstitution. To determine a mechanism for PGE2-mediated suppression of pulmonary host defense post-BMT, roles for inhibitory molecules interleukin-1 receptor associated kinase (IRAK)-M and phosphatase and tensin homolog on chromosome 10 (PTEN) were examined. We found that IRAK-M expression and PTEN phosphatase activity were elevated in BMT AMs relative to control AMs, and this was related to AM overproduction of PGE2. Furthermore, genetic ablation of IRAK-M in the bone marrow of BMT mice restored host defense against P. aeruginosa. Similarly, WT mice transplanted with myeloid-specific PTEN knockout (KO) bone marrow also displayed improved host defense against P. aeruginosa. Despite overproduction of PGE2, AM phagocytosis, killing, and production of proinflammatory mediators were restored in the absence of either IRAK-M or PTEN post-BMT. Overall, these data demonstrate that the absence of either IRAK-M or PTEN in the hematopoietic compartment post-BMT enhances pulmonary host defense and mitigates AM sensitivity to the inhibitory effects of PGE2.