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
Activity of SHIP, Which Prevents Expression of Interleukin 1ß, Is Reduced in Patients With Crohn's Disease.
Ngoh EN, Weisser SB, Lo Y, Kozicky LK, Jen R, Brugger HK, Menzies SC, McLarren KW, Nackiewicz D, van Rooijen N, Jacobson K, Ehses JA, Turvey SE, Sly LM
Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state.
Kozicky LK, Zhao ZY, Menzies SC, Fidanza M, Reid GS, Wilhelmsen K, Hellman J, Hotte N, Madsen KL, Sly LM
The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects.
Ngoh EN, Brugger HK, Monajemi M, Menzies SC, Hirschfeld AF, Del Bel KL, Jacobson K, Lavoie PM, Turvey SE, Sly LM
Impaired NLRP3 inflammasome activity during fetal development regulates IL-1ß production in human monocytes.
Sharma AA, Jen R, Kan B, Sharma A, Marchant E, Tang A, Gadawski I, Senger C, Skoll A, Turvey SE, Sly LM, Côté HC, Lavoie PM
Arginase activity in alternatively activated macrophages protects PI3Kp110d deficient mice from dextran sodium sulfate induced intestinal inflammation.
Weisser SB, Kozicky LK, Brugger HK, Ngoh EN, Cheung B, Jen R, Menzies SC, Samarakoon A, Murray PJ, Lim CJ, Johnson P, Boucher JL, van Rooijen N, Sly LM
Combined immunodeficiency associated with homozygous MALT1 mutations.
McKinnon ML, Rozmus J, Fung SY, Hirschfeld AF, Del Bel KL, Thomas L, Marr N, Martin SD, Marwaha AK, Priatel JJ, Tan R, Senger C, Tsang A, Prendiville J, Junker AK, Seear M, Schultz KR, Sly LM, Holt RA, Patel MS
Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML.
Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Yun H, Görlich K, Wichmann M, Schwarzer A, Preller M, Thol F, Meyer J, Haemmerle R, Struys EA, Jansen EE, Modlich U, Li Z, Sly LM, Geffers R, Lindner R, Manstein DJ
SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitis.
Weisser SB, Brugger HK, Voglmaier NS, McLarren KW, van Rooijen N, Sly LM
A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation.
Ho VW, Leung K, Hsu A, Luk B, Lai J, Shen SY, Minchinton AI, Waterhouse D, Bally MB, Lin W, Nelson BH, Sly LM, Krystal G
SHIP-deficient mice develop spontaneous intestinal inflammation and arginase-dependent fibrosis.
McLarren KW, Cole AE, Weisser SB, Voglmaier NS, Conlin VS, Jacobson K, Popescu O, Boucher JL, Sly LM
Alternative activation of macrophages by IL-4 requires SHIP degradation.
Weisser SB, McLarren KW, Voglmaier N, van Netten-Thomas CJ, Antov A, Flavell RA, Sly LM
SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.
Kuroda E, Antignano F, Ho VW, Hughes MR, Ruschmann J, Lam V, Kawakami T, Kerr WG, McNagny KM, Sly LM, Krystal G
Tyrosine phosphorylation of SHIP promotes its proteasomal degradation.
Ruschmann J, Ho V, Antignano F, Kuroda E, Lam V, Ibaraki M, Snyder K, Kim C, Flavell RA, Kawakami T, Sly L, Turhan AG, Krystal G
The p110a and p110ß isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells.
Ivison SM, Khan MA, Graham NR, Shobab LA, Yao Y, Kifayet A, Sly LM, Steiner TS
Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal.
Heuser 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
SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils.
Kuroda E, Ho V, Ruschmann J, Antignano F, Hamilton M, Rauh MJ, Antov A, Flavell RA, Sly LM, Krystal G
SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.
Sly LM, Hamilton MJ, Kuroda E, Ho VW, Antignano FL, Omeis SL, van Netten-Thomas CJ, Wong D, Brugger HK, Williams O, Feldman ME, Houseman BT, Fiedler D, Shokat KM, Krystal G
IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species.
Sly LM, Kalesnikoff J, Lam V, Wong D, Song C, Omeis S, Chan K, Lee CW, Siraganian RP, Rivera J, Krystal G
Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.
Argiropoulos B, Palmqvist L, Yung E, Kuchenbauer F, Heuser M, Sly LM, Wan A, Krystal G, Humphries RK
Monocyte p110alpha phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production.
Lee JS, Nauseef WM, Moeenrezakhanlou A, Sly LM, Noubir S, Leidal KG, Schlomann JM, Krystal G, Reiner NE
The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia.
Palmqvist L, Argiropoulos B, Pineault N, Abramovich C, Sly LM, Krystal G, Wan A, Humphries RK
SHIP represses the generation of alternatively activated macrophages.
Rauh MJ, Ho V, Pereira C, Sham A, Sly LM, Lam V, Huxham L, Minchinton AI, Mui A, Krystal G
The role of SHIP1 in macrophage programming and activation.
Rauh MJ, Sly LM, Kalesnikoff J, Hughes MR, Cao LP, Lam V, Krystal G
SHIP, SHIP2, and PTEN activities are regulated in vivo by modulation of their protein levels: SHIP is up-regulated in macrophages and mast cells by lipopolysaccharide.
Sly LM, Rauh MJ, Kalesnikoff J, Büchse T, Krystal G
The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2.
López M, Sly LM, Luu Y, Young D, Cooper H, Reiner NE
Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages.
Rauh MJ, Kalesnikoff J, Hughes M, Sly L, Lam V, Krystal G
Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1.
Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR
The role of SHIP in cytokine-induced signaling.
Kalesnikoff J, Sly LM, Hughes MR, Büchse T, Rauh MJ, Cao LP, Lam V, Mui A, Huber M, Krystal G
Salmonella enterica serovar Typhimurium periplasmic superoxide dismutases SodCI and SodCII are required for protection against the phagocyte oxidative burst.
Sly LM, Guiney DG, Reiner NE
1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase.
Sly LM, Lopez M, Nauseef WM, Reiner NE
1alpha,25-dihydroxyvitamin D(3)-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex.
Hmama Z, Nandan D, Sly L, Knutson KL, Herrera-Velit P, Reiner NE
Reconstitution of glucose uptake and chemotaxis in Pseudomonas aeruginosa glucose transport defective mutants.
Sly LM, Worobec EA, Perkins RE, Phibbs PV
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.
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.
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.Honours & Awards
The G. Jeanette Thorbecke New Investigator Award from the Society for Leukocyte Biology (2012)
Canadian Association of Gastroenterology and Canadian Institutes of Health Research New Investigator Award (2009-2013)
Michael Smith Foundation for Health Research Scholar Award (2012-2021)Research Group Members
Mahdis Monajemi, Doctoral Student
Susan Menzies, Lab Manager/Research Assistant Technician
Peter Dobranowski, Grad Student -Masters