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Mechanisms of consumptive anemia of inflammation: Roles for interferon-gamma and hemophagocytosis

Zoller, Erin

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2011, PhD, University of Cincinnati, Medicine: Immunology.
Anemia is a widespread and potentially serious clinical problem. Anemia caused by inflammation has been recognized for over 100 years, however the mechanisms behind anemia during acute inflammation are poorly understood. For clues as to how acute anemia during inflammation might develop, we looked to a disease called hemophagocytic lymphohistiocytosis (HLH). HLH a disorder characterized by severe, acute anemia and cytopenias in the context of exaggerated inflammation. These patients have activated, proliferating and infiltrating macrophages that have engulfed RBCs, a process called hemophagocytosis. Interferon-gamma (IFN-γ) is an inflammatory cytokine and activator of macrophages made in great excess in many HLH patients and correlated with disease severity and poor prognosis. IFN-γ has been shown to be a uniquely necessary cytokine for anemia development in mouse models of HLH. We hypothesized that IFN-γ is sufficient to cause acute consumptive anemia by directly activating macrophages to hemophagocytose blood components. We developed an in vivo IFN-γ infusion system using surgically placed osmotic pumps in mice, and we determined the extent of anemia by measuring blood hemoglobin concentration. We demonstrate that IFN-γ is sufficient, in a dose dependent manner, to cause severe and rapidly developing anemia in wild-type mice. We term this anemia ‘consumptive anemia of inflammation’ (CAI). In addition, we observed hemophagocytosis by macrophages in the tissues via microscopy and flow cytometry. We also studied IFN-γ infusion of Macrophages Insensitive to Interferon-Gamma (MIIG) mice, in which the only cell type that cannot respond to IFN-γ are the macrophages. Results revealed that IFN-γ must act on the macrophages to cause either hemophagocytosis or CAI. Our data strongly suggest that hemophagocytosis by macrophages is the main mechanism of IFN-γ driven CAI. We next aimed to examine the entirely unknown mechanisms behind the hemophagocytic process. We determined IFN-γ driven hemophagocytosis is a macropinocytic process, similar in appearance to another macropinocytic process called efferocytosis, or uptake of apoptotic cells. The similarities between hemophagocytosis and efferocytosis, along with our studies demonstrating that IFN-γ increases efferocytosis, led us to hypothesize that the two processes might share mechanisms. We examined hemophagaocytosis in terms of three important mechanisms of efferocytosis: 1) cell tethering, 2) “eat me” signals and 3) “don’t eat me” signals. We show that IFN-γ causes increased tethering of RBCs to macrophages. Tethering is accompanied by increased macrophage sensitivity to “eat me” signals. This data suggests that IFN-γ infusion causes macrophages to lower their threshold for “eat me” signals to induce engulfment. We also found that C57BL/6J mice are a strain “susceptible” to severe CAI after IFN-γ infusion, whereas 129/Sv mice have a “resistant” phenotype. Using F1 and F2 crosses of these two strains, we concluded that the susceptible CAI phenotype is autosomal recessive and most likely due to two loci dependent on one another. Collectively, this work uncovers previously unknown mechanisms of acute anemia of inflammation. We demonstrate the sufficiency of a single inflammatory cytokine to cause severe acute anemia and for the first time, identify a pathological role for hemophagocytosis in disease.
Michael Jordan, MD (Committee Chair)
Claire Chougnet, PhD (Committee Member)
Hector Wong, MD (Committee Member)
Gurjit Hershey, MD,PhD (Committee Member)
Marsha Wills-Karp, PhD (Committee Member)
212 p.

Recommended Citations

Citations

  • Zoller, E. (2011). Mechanisms of consumptive anemia of inflammation: Roles for interferon-gamma and hemophagocytosis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312483784

    APA Style (7th edition)

  • Zoller, Erin. Mechanisms of consumptive anemia of inflammation: Roles for interferon-gamma and hemophagocytosis. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312483784.

    MLA Style (8th edition)

  • Zoller, Erin. "Mechanisms of consumptive anemia of inflammation: Roles for interferon-gamma and hemophagocytosis." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312483784

    Chicago Manual of Style (17th edition)