Type 1 Interferons Suppress Accelerated Osteoclastogenesis and Prevent Loss of Bone Mass During Systemic Inflammatory Responses to Pneumocystis Lung Infection

Abstract

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.

Modulation of Inflammasome-Mediated Pulmonary Immune Activation by Type I IFNs Protects Bone Marrow Homeostasis during Systemic Responses to Pneumocystis Lung Infection

“…This crisis is associated with similar bone marrow cytokine-deviations previously noted in IFrag −/− mice (62) that are consistent with neutrophil apoptosis (76, 77) and include up-regulation of TNF-α and TRAIL. However, in contrast to IFrag −/− mice, lymphocyte-competent IFNAR −/− mice retain hematopoietic progenitor activity with the ability to replenish transiently lost cells, although significant extramedullary hematopoiesis serves as additional evidence of bone marrow stress.…”

“…However, consistent with evidence of bone marrow stress, and different from IFrag −/− mice, extramedullary hematopoiesis in the spleen was suggested by increased spleen size and could be confirmed by increased hematopoietic progenitor activity when splenocytes were placed in CFU assays (Figure 1 Panel C). Furthermore, and consistent with bone marrow depression, IFNAR −/− mice demonstrated a deviated, infection-induced bone marrow cytokine profile previously shown to be associated with bone marrow failure in IFrag −/− mice (62). This included a transient up-regulation of pro-inflammatory and pro-apoptotic cytokines such as TNF-α, IL-1β and TRAIL (Figure 2 A-C).…”

“…As previously published, Pneumocystis lung infection elicits a strong but transient systemic type-I-IFN-response with elevated serum IFNα levels in wildtype and RAG −/− mice (62). Here we further evaluated whether specific immune mediators were elicited systemically and uniquely in IFrag −/− and IFNAR −/− mice in response to Pneumocystis lung infection that could be linked to the induction of bone marrow stress.…”

“…This is due to accelerated apoptosis of maturing granulocytes combined with lack of replenishment from early progenitors (61). Induction of bone marrow failure in IFrag −/− mice is associated with the deregulated expression of pro-inflammatory and pro-apoptotic cytokines (e.g TNF-a, IL-1, TRAIL) and exuberant ROS-induction in the bone marrow (61, 62). However, the communication pathway initiated between lung and bone marrow resulting in the induction of bone marrow failure in response to this strictly pulmonary infection has been unclear.…”

Neutropenia during HIV Infection: Adverse Consequences and Remedies

“…Pneumocystis carinii is an extracellular fungal pathogen. Pneumocystis infection promotes osteoclastogenesis along with bone marrow failure through disruption of type I interferon signaling and induction of osteoclastogenic factors, including the receptor-activated nuclear factor- κ B ligand and the proapoptotic factor tumor necrosis factor-related apoptosis-inducing ligand, in conjunction with their shared decoy receptor osteoprotegerinas [133, 134]. …”