Bio

Honors & Awards


  • Graduate Research Fellowship, National Science Foundation (2016)
  • Undergraduate Research Fellowship, American Heart Association (2013)
  • Research Internship in Science and Engineering, German Academic Exchange Service (2012)
  • Sidney Fine Teaching Award, University of Michigan College of Literature, Science, and the Arts Honors Program (2014)
  • Departmental High Honors, University of Michigan Program in Biology (2014)
  • High Distinction in the College, University of Michigan College of Literature, Science, and the Arts (2014)
  • Phi Beta Kappa Society, Alpha of Michigan Chapter (2014)
  • Honor Society of Phi Kappa Phi, University of Michigan Chapter (2013)

Education & Certifications


  • PhD, Stanford University, Immunology
  • BS, University of Michigan, Cellular and Molecular Biology (2014)

Professional

Work Experience


  • Undergraduate Research Assistant, University of Michigan (9/2010 - 8/2014)

    Mentor: Dr. Peter A. Ward
    Thesis: Catecholamines induce a regulatory macrophage phenotype and confer protection during acute lung injury and endotoxemia via activation of the β2 adrenergic receptor

    Location

    Ann Arbor, MI

  • Undergraduate Teaching Assistant, University of Michigan (9/2013 - 5/2014)

    Introductory Biology - Molecular, Cellular, and Developmental

    Location

    Ann Arbor, MI

Publications

Journal Articles


  • Induction of M2 Regulatory Macrophages through the β2-Adrenergic Receptor with Protection during Endotoxemia and Acute Lung Injury. Journal of innate immunity Grailer, J. J., Haggadone, M. D., Sarma, J. V., Zetoune, F. S., Ward, P. A. 2014

    Abstract

    The main drivers of acute inflammation are macrophages, which are known to have receptors for catecholamines. Based on their function, macrophages are broadly categorized as having either M1 (proinflammatory) or M2 phenotypes (anti-inflammatory). In this study, we investigated catecholamine-induced alterations in the phenotype of activated macrophages. In the presence of lipopolysaccharide (LPS), mouse peritoneal macrophages acquired an M1 phenotype. However, the copresence of LPS and either epinephrine or norepinephrine resulted in a strong M2 phenotype including high levels of arginase-1 and interleukin-10, and a reduced expression of M1 markers. Furthermore, epinephrine enhanced macrophage phagocytosis and promoted type 2 T-cell responses in vitro, which are known features of M2 macrophages. Analysis of M2 subtype-specific markers indicated that LPS and catecholamine-cotreated macrophages were not alternatively activated but were rather of the regulatory macrophage subtype. Interestingly, catecholamines signaled through the β2-adrenergic receptor but not the canonical cAMP/protein kinase A signaling pathway. Instead, the M2 pathway required an intact phosphoinositol 3-kinase pathway. Blockade of the β2-adrenergic receptor reduced survival and enhanced injury in mouse models of endotoxemia and LPS-induced acute lung injury, respectively. These results demonstrate a role for the β2-adrenergic receptor in promoting the M2 macrophage phenotype. © 2014 S. Karger AG, Basel.

    View details for DOI 10.1159/000358524

    View details for PubMedID 24642449

  • Critical Role for the NLRP3 Inflammasome during Acute Lung Injury. Journal of immunology (Baltimore, Md. : 1950) Grailer, J. J., Canning, B. A., Kalbitz, M., Haggadone, M. D., Dhond, R. M., Andjelkovic, A. V., Zetoune, F. S., Ward, P. A. 2014; 192 (12): 5974-83

    Abstract

    The inflammasome is a key factor in innate immunity and senses soluble pathogen and danger-associated molecular patterns as well as biological crystals (urate, cholesterol, etc.), resulting in expression of IL-1β and IL-18. Using a standard model of acute lung injury (ALI) in mice featuring airway instillation of LPS, ALI was dependent on availability of NLRP3 as well as caspase-1, which are known features of the NLRP3 inflammasome. The appearance of IL-1β, a product of NLRP3 inflammasome activation, was detected in bronchoalveolar lavage fluids (BALF) in a macrophage- and neutrophil-dependent manner. Neutrophil-derived extracellular histones appeared in the BALF during ALI and directly activated the NLRP3 inflammasome. Ab-mediated neutralization of histones significantly reduced IL-1β levels in BALF during ALI. Inflammasome activation by extracellular histones in LPS-primed macrophages required NLRP3 and caspase-1 as well as extrusion of K(+), increased intracellular Ca(2+) concentration, and generation of reactive oxygen species. NLRP3 and caspase-1 were also required for full extracellular histone presence during ALI, suggesting a positive feedback mechanism. Extracellular histone and IL-1β levels in BALF were also elevated in C5a-induced and IgG immune complex ALI models, suggesting a common inflammatory mechanism. These data indicate an interaction between extracellular histones and the NLRP3 inflammasome, resulting in ALI. Such findings suggest novel targets for treatment of ALI, for which there is currently no known efficacious drug.

    View details for DOI 10.4049/jimmunol.1400368

    View details for PubMedID 24795455

  • The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation EUROPEAN JOURNAL OF IMMUNOLOGY Bosmann, M., Haggadone, M. D., Zetoune, F. S., Sarma, J. V., Ward, P. A. 2013; 43 (7): 1907-1913

    Abstract

    The complement activation product, C5a, is a key factor for regulation of inflammatory responses. C5a and C5adesArg bind to their receptors, C5aR and C5L2, but the functional roles of C5L2 remain controversial. We screened the patterns of 23 inflammatory mediators in cultures of LPS-activated mouse peritoneal elicited macrophages (PEMs) in the presence or absence of recombinant mouse C5a. Production of most mediators studied was suppressed by C5a, whereas G-CSF production was enhanced. G-CSF gene expression and secretion from PEMs was amplified two- to threefold by C5a in a dose- and time-dependent fashion. The degradation product C5adesArg promoted lower levels of G-CSF. The effects of C5a on G-CSF were associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5a did not enhance G-CSF production in cultures of PEMs from either C5aR- or C5L2-deficient mice, indicating that both C5a receptors are indispensable for mediating the effects of C5a in the production of G-CSF. Finally, G-CSF levels in plasma during polymicrobial sepsis after cecal ligation and puncture were substantially lower in C5aR- or C5L2-deficient mice as compared with that in C57BL/6J WT mice. These findings elucidate the functional characteristics of the C5L2 receptor during the acute inflammatory response.

    View details for DOI 10.1002/eji.201243075

    View details for Web of Science ID 000327695500025

    View details for PubMedID 23575697

  • Regulation of IL-17 family members by adrenal hormones during experimental sepsis in mice. American journal of pathology Bosmann, M., Meta, F., Ruemmler, R., Haggadone, M. D., Sarma, J. V., Zetoune, F. S., Ward, P. A. 2013; 182 (4): 1124-1130

    Abstract

    Severe sepsis is a life-threatening disease that causes major morbidity and mortality. Catecholamines and glucocorticoids often have been used for the treatment of sepsis. Several recent studies have suggested a potential role of IL-17 during the development and progression of sepsis in small animal models. In this study, the cross-talk of catecholamines and glucocorticoids with members of the IL-17 family was investigated during sepsis in C57BL/6 mice. The concentrations in plasma of IL-17A, IL-17F, and the IL-17AF heterodimer all were increased greatly in mice after endotoxemia or cecal ligation and puncture as compared with sham mice. Surprisingly, when compared with IL-17A (487 pg/mL), the concentrations of IL-17F (2361 pg/mL) and the heterodimer, IL-17AF (5116 pg/mL), were much higher 12 hours after endotoxemia. After surgical removal of the adrenal glands, mice had much higher mortality after endotoxemia or cecal ligation and puncture. The absence of endogenous adrenal gland hormones (cortical and medullary) was associated with 3- to 10-fold higher concentrations of IL-17A, IL-17F, IL-17AF, and IL-23. The addition of adrenaline, noradrenaline, hydrocortisone, or dexamethasone to lipopolysaccharide-activated peritoneal macrophages dose-dependently suppressed the expression and release of IL-17s. The production of IL-17s required activation of c-Jun-N-terminal kinase, which was antagonized by both catecholamines and glucocorticoids. These data provide novel insights into the molecular mechanisms of immune modulation by catecholamines and glucocorticoids during acute inflammation.

    View details for DOI 10.1016/j.ajpath.2013.01.005

    View details for PubMedID 23499051

  • Complement Activation Product C5a Is a Selective Suppressor of TLR4-Induced, but Not TLR3-Induced, Production of IL-27(p28) from Macrophages JOURNAL OF IMMUNOLOGY Bosmann, M., Haggadone, M. D., Hemmila, M. R., Zetoune, F. S., Sarma, J. V., Ward, P. A. 2012; 188 (10): 5086-5093

    Abstract

    There is accumulating evidence that the complement activation product, C5a, can orchestrate cellular immune functions. IL-27(p28/EBI3) is an emerging key player essential for regulating inflammatory responses and T cells. In this article, we report that C5a robustly suppressed IL-27(p28) gene expression and release in peritoneal macrophages. These cells from C57BL/6J mice abundantly produced IL-27(p28) after engagement of either the TLR3 (polyinosinic-polycytidylic acid) or TLR4 (LPS) receptor. Genetic deficiency of either TLR4 or LBP completely incapacitated the ability of macrophages to secrete IL-27(p28) in response to LPS. IL-27(p28)-producing macrophages also expressed the C5aR receptor, thus displaying an IL-27(p28)(+)F4/80(+)C5aR(+) phenotype. C5a suppressed IL-27(p28) in LPS-stimulated macrophages via interactions with the C5aR receptor rather than the C5L2 receptor. After endotoxemia, C5aR(-/-) mice displayed higher plasma levels of IL-27(p28) compared with C57BL/6J mice. C5a did not affect the release of IL-27(p28) or the frequency of IL-27(p28)(+)F4/80(+) macrophages after engagement of TLR3. Mechanistically, LPS activated both the NF-κB and the PI3K/Akt pathways, whereas C5a activated only the PI3K/Akt pathway. Engagement of PI3K/Akt was inhibitory for IL-27(p28) production, because PI3K/Akt pharmacologic blockade resulted in increased amounts of IL-27(p28) and reversed the suppressive effects of C5a. Blockade of PI3K/Akt in endotoxemic C57BL/6J mice resulted in higher generation of IL-27(p28). In contrast, the PI3K/Akt pathway was not involved in TLR3-mediated release of IL-27(p28). These data provide new evidence about how complement activation may selectively interfere with production of T cell regulatory cytokines by APCs in the varying contexts of either bacterial (TLR4 pathway) or viral (TLR3 pathway) infection.

    View details for DOI 10.4049/jimmunol.1102914

    View details for Web of Science ID 000303634300041

    View details for PubMedID 22491257

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