Bio

Honors & Awards


  • Canadian Institutes of Health Research Fellow, Canadian Institutes of Health Research (2014-2017)

Publications

All Publications


  • iRhom2 Regulation of TACE Controls TNF-Mediated Protection Against Listeria and Responses to LPS SCIENCE McIlwain, D. R., Lang, P. A., Maretzky, T., Hamada, K., Ohishi, K., Maney, S. K., Berger, T., Murthy, A., Duncan, G., Xu, H. C., Lang, K. S., Haeussinger, D., Wakeham, A., Itie-Youten, A., Khokha, R., Ohashi, P. S., Blobel, C. P., Mak, T. W. 2012; 335 (6065): 229-232

    Abstract

    Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-? (TNF?), which is shed from the plasma membrane after cleavage by the TNF? convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNF? shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNF? in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

    View details for DOI 10.1126/science.1214448

    View details for Web of Science ID 000299033100056

    View details for PubMedID 22246778

  • Neurological, Cognitive, and Psychological Findings Among Survivors of Ebola Virus Disease From the 1995 Ebola Outbreak in Kikwit, Democratic Republic of Congo: A Cross-sectional Study CLINICAL INFECTIOUS DISEASES Kelly, J., Hoff, N. A., Spencer, D., Musene, K., Bramble, M. S., McIlwain, D., Okitundu, D., Porco, T. C., Rutherford, G. W., Glymour, M., Bjornson, Z., Mukadi, P., Okitolonda-Wemakoy, E., Nolan, G. P., Muyembe-Tamfum, J., Rimoin, A. W. 2019; 68 (8): 1388?93

    View details for DOI 10.1093/cid/ciy677

    View details for Web of Science ID 000464937800019

  • Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy. Bioinformatics (Oxford, England) Ghaemi, M. S., DiGiulio, D. B., Contrepois, K., Callahan, B., Ngo, T. T., Lee-McMullen, B., Lehallier, B., Robaczewska, A., Mcilwain, D., Rosenberg-Hasson, Y., Wong, R. J., Quaintance, C., Culos, A., Stanley, N., Tanada, A., Tsai, A., Gaudilliere, D., Ganio, E., Han, X., Ando, K., McNeil, L., Tingle, M., Wise, P., Maric, I., Sirota, M., Wyss-Coray, T., Winn, V. D., Druzin, M. L., Gibbs, R., Darmstadt, G. L., Lewis, D. B., Partovi Nia, V., Agard, B., Tibshirani, R., Nolan, G., Snyder, M. P., Relman, D. A., Quake, S. R., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2019; 35 (1): 95?103

    Abstract

    Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary information: Supplementary data are available at Bioinformatics online.

    View details for PubMedID 30561547

  • Blood-Induced Bone Loss In A Mouse Model Of Hemophilic Arthropathy Is Prevented By Blocking The iRhom2/ADAM17/TNF alpha Pathway Haxaire, C., Hakobyan, N., Panellini, T., Carballo, C., Mcilwain, D., Mak, T. W., Acharya, S., Li, D., Szymonifka, J., Rodeo, S., Song, X., Monette, S., Srivastava, A., Salmon, J., Blobel, C. WILEY. 2018: 369
  • Neurological, cognitive, and psychological findings among survivors of Ebola virus disease from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo: a cross-sectional study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Kelly, J. D., Hoff, N. A., Spencer, D., Musene, K., Bramble, M. S., McIlwain, D., Okitundu, D., Porco, T. C., Rutherford, G. W., Glymour, M. M., Bjornson, Z., Mukadi, P., Okitolonda-Wemakoy, E., Nolan, G. P., Muyembe-Tamfum, J. J., Rimoin, A. W. 2018

    Abstract

    Background: Clinical sequelae of Ebola virus disease (EVD) have not been described more than three years post-outbreak. We examined survivors and close contacts from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo (DRC), and determined prevalence of abnormal neurological, cognitive, and psychological findings and their association with EVD survivorship.Methods: From August to September 2017, we conducted a cross-sectional study in Kikwit, DRC. Over two decades after the EVD outbreak, we recruited EVD survivors and close contacts from the outbreak to undergo physical examination and culturally adapted versions of the Folstein mini-mental status exam (MMSE) and Goldberg Anxiety and Depression Scale (GADS). We estimated the strength of relationships between EVD survivorship and health outcomes using linear regression models by comparing survivors vs. close contacts, adjusting for age, sex, educational level, marital status and healthcare worker status.Results: We enrolled 20 EVD survivors and 187 close contacts. Among the 20 EVD survivors, 4 (20%) reported at least one abnormal neurological symptom and 3 (15%) had an abnormal neurological examination. Among the 187 close contacts, 14 (11%) reported at least one abnormal neurologic symptom and 9 (5%) had an abnormal neurological examination. EVD survivors had lower mean MMSE and higher mean GADS scores as compared to close contacts (MMSE: adjusted coefficient: -1.85; 95% CI: -3.63, -0.07; GADS: adjusted coefficient: 3.91; 95% CI: 1.76, 6.04).Conclusions: EVD survivors can have lower cognitive scores and more symptoms of depression and anxiety than close contacts more than two decades after Ebola virus outbreaks.

    View details for PubMedID 30107392

  • The xenoestrogens biphenol-A and nonylphenol differentially regulate metalloprotease-mediated shedding of EGFR ligands JOURNAL OF CELLULAR PHYSIOLOGY Urriola-Munoz, P., Li, X., Maretzky, T., McIlwain, D. R., Mak, T. W., Reyes, J. G., Blobel, C. P., Moreno, R. D. 2018; 233 (3): 2247?56

    View details for DOI 10.1002/jcp.26097

    View details for Web of Science ID 000433519300042

  • NEUROLOGICAL, COGNITIVE, AND PSYCHOLOGICAL FINDINGS AMONG SURVIVORS OF EBOLA VIRUS DISEASE FROM THE 1995 KIKWIT OUTBREAK IN DEMOCRATIC REPUBLIC OF CONGO: A CROSS-SECTIONAL STUDY Kelly, J., Hoff, N., Spencer, D., Bramble, M., McIlwain, D., Musene, K., Okitolonda, E., Porco, T., Rutherford, G., Glymour, M., Mukadi, P., Rimoin, A. AMER SOC TROP MED & HYGIENE. 2018: 214
  • The xenoestrogens biphenol-A and nonylphenol differentially regulate metalloprotease-mediated shedding of EGFR ligands. Journal of cellular physiology Urriola-Muñoz, P., Li, X., Maretzky, T., McIlwain, D. R., Mak, T. W., Reyes, J. G., Blobel, C. P., Moreno, R. D. 2018; 233 (3): 2247?56

    Abstract

    The xenoestrogens bisphenol-A (BPA) and nonylphenol (NP) are endocrine disruptors used in the plastic polymer industry to manufacture different products for human use. Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor ? (TNF-?). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR-ligands. We report that BPA and NP can stimulate the release of the ADAM17-substrates HB-EGF and TGF-?. In cells lacking ADAM17 (Adam17-/- mEFs) BPA-stimulated release of HB-EGF, but not TGF-?, was strongly reduced, whereas NP-stimulated shedding of HB-EGF and TGF-? was completely abolished. Inactivation of both ADAM17 and the related ADAM10 (Adam10/17-/- mEFs) completely prevented the release of these substrates. In the absence of iRhom1, BPA- or NP-stimulated release of HB-EGF or TGF-? was comparable to wild-type control mEFs, conversely the BPA-induced release of HB-EGF was abolished in iRhom2-/- mEFs. The defect in shedding of HB-EGF in iRhom2-/- mEF cells could be rescued by overexpressing iRhom2. Interestingly, the NP-stimulated release of HB-EGF was not affected by the absence of iRhom2, suggesting that NP could potentially activate both ADAM10 and ADAM17. We tested this hypothesis using betacellulin (BTC), an EGFR-ligand that is a substrate for ADAM10. We found that NP, but not BPA stimulated the release of BTC in Adam17-/- , iRhom2-/- , or iRhom1/2-/- , but not in Adam10/17-/- cells. Taken together, our results suggest that BPA and NP stimulate the release of EGFR-ligands by differentially activating ADAM17 or ADAM10. The identification of specific effects of these endocrine disruptors on ADAM10 and ADAM17 will help to provide a better understanding of their roles in cell signaling and proinflammatory processes, and provide new potential targets for treatment of reproductive or inflammatory diseases such as asthma or breast cancer that are promoted by xenoestrogens.

    View details for PubMedID 28703301

    View details for PubMedCentralID PMC5705578

  • iRhom2 Deficiency Protects Fcgr2b-/- Lupus-Prone Mice from Kidney Damage By Modulating ADAM17-Dependent Shedding of TNF-alpha and EGFR Ligand Qing, X., Chinenov, Y., Redecha, P. M., Madaio, M., Issuree, P., McIlwain, D., Mak, T., Blobel, C., Salmon, J. E. WILEY. 2017
  • An immune clock of human pregnancy. Science immunology Aghaeepour, N., Ganio, E. A., Mcilwain, D., Tsai, A. S., Tingle, M., Van Gassen, S., Gaudilliere, D. K., Baca, Q., McNeil, L., Okada, R., Ghaemi, M. S., Furman, D., Wong, R. J., Winn, V. D., Druzin, M. L., El-Sayed, Y. Y., Quaintance, C., Gibbs, R., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Tibshirani, R., Nolan, G. P., Lewis, D. B., Angst, M. S., Gaudilliere, B. 2017; 2 (15)

    Abstract

    The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.

    View details for PubMedID 28864494

  • iRhom2 regulates CSF1R cell surface expression and non-steady state myelopoiesis in mice EUROPEAN JOURNAL OF IMMUNOLOGY Qing, X., Rogers, L. D., Mortha, A., Lavin, Y., Redecha, P., Issuree, P. D., Maretzky, T., Merad, M., McIlwain, D. R., Mak, T. W., Overall, C. M., Blobel, C. P., Salmon, J. E. 2016; 46 (12): 2737-2748

    Abstract

    CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells. In iRhom2-/- mice, we found constitutive accumulation of membrane-bound CSF1R on myeloid cells at steady state, although cell numbers of these populations were not altered. However, in the context of mixed bone marrow (BM) chimera, under competitive pressure, iRhom2-/- BM progenitor-derived monocytes, tissue macrophages and lung DCs showed a repopulation advantage over those derived from wild-type (WT) BM progenitors, suggesting enhanced CSF1R signaling in the absence of iRhom2. In vitro experiments indicate that iRhom2-/- Lin(-) SCA-1(+) c-Kit(+) (LSKs) cells, but not granulocyte-macrophage progenitors (GMPs), had faster growth rates than WT cells in response to CSF1. Our results shed light on an important role of iRhom2/ADAM17 pathway in regulation of CSF1R shedding and repopulation of monocytes, macrophages and DCs.

    View details for DOI 10.1002/eji.201646482

    View details for Web of Science ID 000392940400013

    View details for PubMedID 27601030

    View details for PubMedCentralID PMC5149455

  • iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Li, X., Maretzky, T., Weskamp, G., Monette, S., Qing, X., Issuree, P. D., Crawford, H. C., McIlwain, D. R., Mak, T. W., Salmon, J. E., Blobel, C. P. 2015; 112 (19): 6080-6085

    Abstract

    The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17(-/-) mice die perinatally with open eyes, like Egfr(-/-) mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2(-/-) mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2(-/-) double knockout mice resemble Adam17(-/-) and Egfr(-/-) mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2(-/-) tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFR-dependent pathologies.

    View details for DOI 10.1073/pnas.1505649112

    View details for Web of Science ID 000354390600066

    View details for PubMedID 25918388

    View details for PubMedCentralID PMC4434755

  • Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection. Journal of virology Xu, H. C., Huang, J., Khairnar, V., Duhan, V., Pandyra, A. A., Grusdat, M., Shinde, P., McIlwain, D. R., Maney, S. K., Gommerman, J., Löhning, M., Ohashi, P. S., Mak, T. W., Pieper, K., Sic, H., Speletas, M., Eibel, H., Ware, C. F., Tumanov, A. V., Kruglov, A. A., Nedospasov, S. A., Häussinger, D., Recher, M., Lang, K. S., Lang, P. A. 2015; 89 (9): 4748-4759

    Abstract

    The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

    View details for DOI 10.1128/JVI.02976-14

    View details for PubMedID 25673724

  • Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169(+) Macrophage Function during Viral Infection JOURNAL OF VIROLOGY Xu, H. C., Huang, J., Khairnar, V., Duhan, V., Pandyra, A. A., Grusdat, M., Shinde, P., McIlwain, D. R., Maney, S. K., Gommerman, J., Loehning, M., Ohashi, P. S., Mak, T. W., Pieper, K., Sic, H., Speletas, M., Eibel, H., Ware, C. F., Tumanov, A. V., Kruglov, A. A., Nedospasov, S. A., Haeussinger, D., Recher, M., Lang, K. S., Lang, P. A. 2015; 89 (9): 4748-4759
  • T-cell STAT3 is required for the maintenance of humoral immunity to LCMV. European journal of immunology McIlwain, D. R., Grusdat, M., Pozdeev, V. I., Xu, H. C., Shinde, P., Reardon, C., Hao, Z., Beyer, M., Bergthaler, A., Häussinger, D., Nolan, G. P., Lang, K. S., Lang, P. A. 2015; 45 (2): 418-427

    Abstract

    STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T-cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T-follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long-term humoral immunity to viral infections.

    View details for DOI 10.1002/eji.201445060

    View details for PubMedID 25393615

  • T-cell STAT3 is required for the maintenance of humoral immunity to LCMV. European journal of immunology McIlwain, D. R., Grusdat, M., Pozdeev, V. I., Xu, H. C., Shinde, P., Reardon, C., Hao, Z., Beyer, M., Bergthaler, A., Häussinger, D., Nolan, G. P., Lang, K. S., Lang, P. A. 2015; 45 (2): 418-427

    Abstract

    STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T-cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T-follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long-term humoral immunity to viral infections.

    View details for DOI 10.1002/eji.201445060

    View details for PubMedID 25393615

  • Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17. Science signaling Maney, S. K., McIlwain, D. R., Polz, R., Pandyra, A. A., Sundaram, B., Wolff, D., Ohishi, K., Maretzky, T., Brooke, M. A., Evers, A., Vasudevan, A. A., Aghaeepour, N., Scheller, J., Münk, C., Häussinger, D., Mak, T. W., Nolan, G. P., Kelsell, D. P., Blobel, C. P., Lang, K. S., Lang, P. A. 2015; 8 (401): ra109-?

    Abstract

    The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune response and promotes programmed cell death but can also promote sepsis. Catalytically inactive members of the rhomboid family of proteases, iRhom1 and iRhom2, mediate the intracellular transport and maturation of ADAM17. Using a genetic screen, we found that the presence of either iRhom1 or iRhom2 lacking part of their extended amino-terminal cytoplasmic domain (herein referred to as ?N) increases ADAM17 activity, TNFR shedding, and resistance to TNF-induced cell death in fibrosarcoma cells. Inhibitors of ADAM17, but not of other ADAM family members, prevented the effects of iRhom-?N expression. iRhom1 and iRhom2 were functionally redundant, suggesting a conserved role for the iRhom amino termini. Cells from patients with a dominantly inherited cancer susceptibility syndrome called tylosis with esophageal cancer (TOC) have amino-terminal mutations in iRhom2. Keratinocytes from TOC patients exhibited increased TNFR1 shedding compared with cells from healthy donors. Our results explain how loss of the amino terminus in iRhom1 and iRhom2 impairs TNF signaling, despite enhancing ADAM17 activity, and may explain how mutations in the amino-terminal region contribute to the cancer predisposition syndrome TOC.

    View details for DOI 10.1126/scisignal.aac5356

    View details for PubMedID 26535007

  • IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV CELL DEATH AND DIFFERENTIATION Grusdat, M., McIlwain, D. R., Xu, H. C., Pozdeev, V. I., Knievel, J., Crome, S. Q., Robert-Tissot, C., Dress, R. J., Pandyra, A. A., Speiser, D. E., Lang, E., Maney, S. K., Elford, A. R., Hamilton, S. R., Scheu, S., Pfeffer, K., Bode, J., Mittruecker, H., Lohoff, M., Huber, M., Haeussinger, D., Ohashi, P. S., Mak, T. W., Lang, K. S., Lang, P. A. 2014; 21 (7): 1050-1060

    Abstract

    CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity.

    View details for DOI 10.1038/cdd.2014.19

    View details for Web of Science ID 000337234200003

    View details for PubMedID 24531538

  • iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Maretzky, T., McIlwain, D. R., Issuree, P. D., Li, X., Malapeira, J., Amin, S., Lang, P. A., Mak, T. W., Blobel, C. P. 2013; 110 (28): 11433-11438

    Abstract

    Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNF? release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGF?, is not affected in iRhom2(-/-) mEFs but can be strongly reduced by treating iRhom2(-/-) mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2(-/-) mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2(-/-) mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2(-/-) keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.

    View details for DOI 10.1073/pnas.1302553110

    View details for Web of Science ID 000321827000058

    View details for PubMedID 23801765

  • Caspase Functions in Cell Death and Disease COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY McIlwain, D. R., Berger, T., Mak, T. W. 2013; 5 (4)

    Abstract

    Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.

    View details for DOI 10.1101/cshperspect.a008656

    View details for Web of Science ID 000317175200008

    View details for PubMedID 23545416

  • Reactive oxygen species delay control of lymphocytic choriomeningitis virus. Cell death and differentiation Lang, P. A., Xu, H. C., Grusdat, M., McIlwain, D. R., Pandyra, A. A., Harris, I. S., Shaabani, N., HONKE, N., Maney, S. K., Lang, E., Pozdeev, V. I., Recher, M., Odermatt, B., Brenner, D., Häussinger, D., Ohashi, P. S., Hengartner, H., Zinkernagel, R. M., Mak, T. W., Lang, K. S. 2013; 20 (4): 649-658

    Abstract

    Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

    View details for DOI 10.1038/cdd.2012.167

    View details for PubMedID 23328631

  • Involvement of Toso in activation of monocytes, macrophages, and granulocytes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lang, K. S., Lang, P. A., Meryk, A., Pandyra, A. A., Boucher, L., Pozdeev, V. I., Tusche, M. W., Goethert, J. R., Haight, J., Wakeham, A., You-Ten, A. J., McIlwain, D. R., Merches, K., Khairnar, V., Recher, M., Nolan, G. P., Hitoshi, Y., Funkner, P., Navarini, A. A., Verschoor, A., Shaabani, N., Honke, N., Penn, L. Z., Ohashi, P. S., Haeussinger, D., Lee, K., Mak, T. W. 2013; 110 (7): 2593-2598

    Abstract

    Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso-deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso(-/-) mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso(-/-) mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso(-/-) mice succumbed to infections of L. monocytogenes, whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock.

    View details for DOI 10.1073/pnas.1222264110

    View details for Web of Science ID 000315812800047

    View details for PubMedID 23359703

    View details for PubMedCentralID PMC3574925

  • iRHOM2 is a critical pathogenic mediator of inflammatory arthritis JOURNAL OF CLINICAL INVESTIGATION Issuree, P. D., Maretzky, T., McIlwain, D. R., Monette, S., Qing, X., Lang, P. A., Swendeman, S. L., Park-Min, K., Binder, N., Kalliolias, G. D., Yarilina, A., Horiuchi, K., Ivashkiv, L. B., Mak, T. W., Salmon, J. E., Blobel, C. P. 2013; 123 (2): 928-932

    Abstract

    iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-? convertase (TACE), which controls shedding of TNF-? and its biological activity in vivo. TACE is a potential target to treat TNF-?-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-? in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-? in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.

    View details for DOI 10.1172/JCI66168

    View details for Web of Science ID 000314553600045

    View details for PubMedID 23348744

  • Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA McIlwain, D. R., Pan, Q., Reilly, P. T., Elia, A. J., McCracken, S., Wakeham, A. C., Itie-Youten, A., Blencowe, B. J., Mak, T. W. 2010; 107 (27): 12186-12191

    Abstract

    Smg1 is a PI3K-related kinase (PIKK) associated with multiple cellular functions, including DNA damage responses, telomere maintenance, and nonsense-mediated mRNA decay (NMD). NMD degrades transcripts that harbor premature termination codons (PTCs) as a result of events such as mutation or alternative splicing (AS). Recognition of PTCs during NMD requires the action of the Upstream frameshift protein Upf1, which must first be phosphorylated by Smg1. However, the physiological function of mammalian Smg1 is not known. By using a gene-trap model of Smg1 deficiency, we show that this kinase is essential for mouse embryogenesis such that Smg1 loss is lethal at embryonic day 8.5. High-throughput RNA sequencing (RNA-Seq) of RNA from cells of Smg1-deficient embryos revealed that Smg1 depletion led to pronounced accumulation of PTC-containing splice variant transcripts from approximately 9% of genes predicted to contain AS events capable of eliciting NMD. Among these genes are those involved in splicing itself, as well as genes not previously known to be subject to AS-coupled NMD, including several involved in transcription, intracellular signaling, membrane dynamics, cell death, and metabolism. Our results demonstrate a critical role for Smg1 in early mouse development and link the loss of this NMD factor to major and widespread changes in the mammalian transcriptome.

    View details for DOI 10.1073/pnas.1007336107

    View details for Web of Science ID 000279572100028

    View details for PubMedID 20566848

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