• Sly, Laura


    Investigator, BC Children's Hospital
    Associate Professor, Division of Gastroenterology, Department of Pediatrics, University of British Columbia

    Degrees / Designations
    B.Sc., M.Sc., PhD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Lab Phone
    Mailing Address

    BC Children's Hospital Research Institute
    Room A5-142
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas
    • Macrophages
    • Inflammatory bowel diseases
    • Inflammation
    • Innate immune responses

    Macrophages are specialized cells of our immune system.  They provide our first line of defence against invading micro-organisms starting the immune response and are called “killer” macrophages.  When our body has finished killing off unwanted invaders, these macrophages change their function and help in cleaning up the injured area.  These are called “healer” macrophages.  During clean up, macrophages tidy up debris, promote wound healing and scar formation and shut off the immune response.  In some inflammatory diseases, like inflammatory bowel disease, the immune response gets out of control.  Macrophages are the largest producers of tumour necrosis factor alpha in the gut and an antibody directed against this macrophage product is an effective therapy for patients with Crohn’s disease and ulcerative colitis.  The goal of my research is to understand how these macrophages make the switch from “killers” to “healers” with the hope of pushing macrophages to “healers” during inflammatory bowel disease

    Current Projects

    Role of the PI3K pathway in canonical alternative activation of macrophages

    The src homology 2 domain-containing inositol 5'-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) pathway.  In vivo-differentiated SHIP deficient macrophages display a profoundly anergic phenotype and express phenotypic markers of alternative activation independent of canonical skewing by the Th2 cytokine, IL-4.  SHIP protein levels are dramatically reduced when macrophages are skewed to an alternatively activate phenotype by IL-4 suggesting that increased PI3K activity may be required for canonical alternative activation of macrophages as well.  We are currently characterizing the role of the PI3K pathway during canonical alternative activation of macrophages.

    L-arginine metabolism in inflammation and fibrosis

    L-arginine metabolism provides a key switch in macrophage phenotype.  L-arginine can be metabolized by two pathways in macrophages.  In classically activated macrophages during inflammation, the enzyme inducible nitric oxide synthase (iNOS) uses arginine to generate pro-inflammatory nitric oxide (NO).  However, alternatively activated macrophages also express the enzyme arginase.  Arginase metabolizes arginine leading to the production of polyamines, which promote cell growth, and proline, an essential component of collagen that can contribute to fibrosis.  We are currently investigating the role of arginine metabolism by each of these pathways in inflammation and in fibrosis.  

    Macrophage phenotype in inflammatory bowel disease

    Macrophages are critical effector cells in the inflammatory response.  Classically activated macrophages initiate the innate immune response and direct the activity of the acquired immune response.  Upon resolution of inflammation, macrophages convert to an anti-inflammatory phenotype called alternatively activated.  Alternatively activated macrophages promote debris scavenging, tissue remodelling and wound healing.  Intriguingly, macrophages can be manipulated to move back and forth between these two phenotypes.  During inflammatory disorders, like inflammatory bowel disease, switching macrophages to an alternatively activated phenotype, could dampen down inflammation and reduce disease.  We are currently assessing the macrophage phenotype present during inflammatory bowel disease and mechanisms that we could use to switch macrophages to an anti-inflammatory phenotype during disease.         

    Selected Publications
    Generation and characterization of murine alternatively activated macrophages.

    Weisser SB, McLarren KW, Kuroda E, Sly LM. Methods Mol Biol. 2013;946:225-39. doi: 10.1007/978-1-62703-128-8_14.

    Depletion and reconstitution of macrophages in miceWeisser SB, van Rooijen N, Sly LM. J Vis Exp. 2012 Aug 1;(66):4105. doi: 10.3791/4105.

    SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitisWeisser SB, Brugger HK, Voglmaier NS, McLarren KW, van Rooijen N, Sly LM. J Leukoc Biol. 2011 Sep;90(3):483-92. doi: 10.1189/jlb.0311124. Epub 2011 Jun 17.

    SHIP-deficient mice develop spontaneous intestinal inflammation and arginase-dependent fibrosisMcLarren KW, Cole AE, Weisser SB, Voglmaier NS, Conlin VS, Jacobson K, Popescu O, Boucher JL, Sly LM. Am J Pathol. 2011 Jul;179(1):180-8. doi: 10.1016/j.ajpath.2011.03.018. Epub 2011 May 7.

    Alternative activation of macrophages by IL-4 requires SHIP degradationWeisser SB, McLarren KW, Voglmaier N, van Netten-Thomas CJ, Antov A, Flavell RA, Sly LM. Eur J Immunol. 2011 Jun;41(6):1742-53. doi: 10.1002/eji.201041105. Epub 2011 May 13.

    SHIP represses Th2 skewing by inhibiting IL-4 production from basophilsKuroda E, Antignano F, Ho VW, Hughes MR, Ruschmann J, Lam V, Kawakami T, Kerr WG, McNagny KM, Sly LM, Krystal G. J Immunol. 2011 Jan 1;186(1):323-32. doi: 10.4049/jimmunol.1002778. Epub 2010 Dec 3.

    The p110α and p110β isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cellsIvison SM, Khan MA, Graham NR, Shobab LA, Yao Y, Kifayet A, Sly LM, Steiner TS. Mediators Inflamm. 2010;2010. doi:pii: 652098. 10.1155/2010/652098. Epub 2010 Oct 3.

    SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophilsKuroda E, Ho V, Ruschmann J, Antignano F, Hamilton M, Rauh MJ, Antov A, Flavell RA, Sly LM, Krystal G. J Immunol. 2009 Sep 15;183(6):3652-60. doi: 10.4049/jimmunol.0900864. Epub 2009 Aug 26.

    Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewalHeuser M, Sly LM, Argiropoulos B, Kuchenbauer F, Lai C, Weng A, Leung M, Lin G, Brookes C, Fung S, Valk PJ, Delwel R, Löwenberg B, Krystal G, Humphries RK. Blood. 2009 Nov 5;114(19):3983-93. doi: 10.1182/blood-2009-06-227603. Epub 2009 Aug 10.


    Crohn’s and Colitis Foundation of Canada Discovery Research Grants - Project: "Regulatory macrophages in inflammatory bowel disease" (2013-2016)

    CIHR Catalyst Grant - Project: "Crohn`s Disease genetic variants predispose to commensal-driven autoinflammation" (2013)

    CIHR Operating Grant - PA INMD Start Up Funds (bridge funding) - Project: "Macrophages in intestinal disease."

    Honours & Awards

    Canadian Association of Gastroenterology and Canadian Institutes of Health Research New Investigator Award (2009-2013)

    The G. Jeanette Thorbecke New Investigator Award from the Society for Leukocyte Biology (2012)

    Michael Smith Foundation for Health Research Scholar Award (2012-2021)

    CHILD Foundation Research Scholar, 2008

    Research Group Members