Although acquired bone marrow failure (BMF) is considered a T cell-mediated autoimmune disease, possible innate immune defects as a cause for systemic immune deviations in response to otherwise innocuous infections, have not been extensively explored. In this regard we recently demonstrated an important role of type-I-IFNs in protecting hematopoiesis during systemic stress responses to the opportunistic fungal pathogen Pneumocystis in lymphocyte-deficient mice. Mice deficient in both lymphocytes and type-I-IFN-receptor (IFrag−/− mice) develop rapidly progressing BMF due to accelerated bone marrow cell apoptosis associated with innate immune deviations in the bone marrow in response to Pneumocystis lung infection. However, the communication pathway between lung and bone marrow eliciting the induction of BMF in response to this strictly pulmonary infection has been unclear. Here we report that absence of an intact type-I-IFN-system during Pneumocystis lung infection not only causes BMF in lymphocyte-deficient mice but also transient bone marrow stress in lymphocyte-competent mice. This is associated with an exuberant systemic IFN-γ response. IFNγ neutralization prevented Pneumocystis lung infection-induced bone marrow depression in type-I-IFN-receptor-deficient (IFNAR−/−) mice, and prolonged neutrophil survival time in bone marrow from IFrag−/− mice. IL-1β and upstream regulators of IFNγ, IL-12 and IL-18, were also upregulated in lung and serum of IFrag−/− mice. In conjunction there was exuberant inflammasome-mediated caspase-1-activation in pulmonary innate immune cells required for processing of IL-18 and IL-1β. Thus, absence of type-I-IFN-signaling during Pneumocystis lung infection may result in deregulation of inflammasome-mediated pulmonary immune activation causing systemic immune deviations triggering BMF in this model.
HIV infection causes loss of CD4(+) T cells and type 1 interferon (IFN)-producing and IFN-responsive dendritic cells, resulting in immunodeficiencies and susceptibility to opportunistic infections, such as Pneumocystis. Osteoporosis and bone marrow failure are additional unexplained complications in HIV-positive patients and patients with AIDS, respectively. We recently demonstrated that mice that lack lymphocytes and IFN a/b receptor (IFrag(-/-)) develop bone marrow failure after Pneumocystis lung infection, whereas lymphocyte-deficient, IFN α/β receptor-competent mice (RAG(-/-)) had normal hematopoiesis. Interestingly, infected IFrag(-/-) mice also exhibited bone fragility, suggesting loss of bone mass. We quantified bone changes and evaluated the potential connection between progressing bone fragility and bone marrow failure after Pneumocystis lung infection in IFrag(-/-) mice. We found that Pneumocystis infection accelerated osteoclastogenesis as bone marrow failure progressed. This finding was consistent with induction of osteoclastogenic factors, including receptor-activated nuclear factor-κB ligand and the proapoptotic factor tumor necrosis factor-related apoptosis-inducing ligand, in conjunction with their shared decoy receptor osteoprotegerin, in the bone marrow of infected IFrag(-/-) mice. Deregulation of this axis has also been observed in HIV-positive individuals. Biphosphonate treatment of IFrag(-/-) mice prevented bone loss and protected loss of hematopoietic precursor cells that maintained activity in vitro but did not prevent loss of mature neutrophils. Together, these data show that bone loss and bone marrow failure are partially linked, which suggests that the deregulation of the receptor-activated nuclear factor-κB ligand/osteoprotegerin/tumor necrosis factor-related apoptosis-inducing ligand axis may connect the two phenotypes in our model.
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