Overview

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

Publications

Activity of SHIP, Which Prevents Expression of Interleukin 1ß, Is Reduced in Patients With Crohn's Disease.
Ngoh EN and Weisser SB and Lo Y and Kozicky LK and Jen R and Brugger HK and Menzies SC and McLarren KW and Nackiewicz D and van Rooijen N and Jacobson K and Ehses JA and Turvey SE and Sly LM
DOI: 10.1053/j.gastro.2015.09.049
PubMed: 26481854
02/2016

a-Integrin expression and function modulates presentation of cell surface calreticulin.
Liu CC and Leclair P and Monajemi M and Sly LM and Reid GS and Lim CJ
DOI: 10.1038/cddis.2016.176
PubMed: 27310876
2016

Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state.
Kozicky LK and Zhao ZY and Menzies SC and Fidanza M and Reid GS and Wilhelmsen K and Hellman J and Hotte N and Madsen KL and Sly LM
DOI: 10.1189/jlb.3vma0315-078r
PubMed: 26216934
12/2015

The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects.
Ngoh EN and Brugger HK and Monajemi M and Menzies SC and Hirschfeld AF and Del Bel KL and Jacobson K and Lavoie PM and Turvey SE and Sly LM
DOI: 10.1038/gene.2015.30
PubMed: 26226011
10/2015

Phosphatase regulation of macrophage activation.
Kozicky LK and Sly LM
DOI: 10.1016/j.smim.2015.07.001
PubMed: 26216598
08/2015

Impaired NLRP3 inflammasome activity during fetal development regulates IL-1ß production in human monocytes.
Sharma AA and Jen R and Kan B and Sharma A and Marchant E and Tang A and Gadawski I and Senger C and Skoll A and Turvey SE and Sly LM and Côté HC and Lavoie PM
DOI: 10.1002/eji.201444707
PubMed: 25311115
01/2015

Arginase activity in alternatively activated macrophages protects PI3Kp110d deficient mice from dextran sodium sulfate induced intestinal inflammation.
Weisser SB and Kozicky LK and Brugger HK and Ngoh EN and Cheung B and Jen R and Menzies SC and Samarakoon A and Murray PJ and Lim CJ and Johnson P and Boucher JL and van Rooijen N and Sly LM
DOI: 10.1002/eji.201343981
PubMed: 25124254
11/2014

Combined immunodeficiency associated with homozygous MALT1 mutations.
McKinnon ML and Rozmus J and Fung SY and Hirschfeld AF and Del Bel KL and Thomas L and Marr N and Martin SD and Marwaha AK and Priatel JJ and Tan R and Senger C and Tsang A and Prendiville J and Junker AK and Seear M and Schultz KR and Sly LM and Holt RA and Patel MS
DOI: 10.1016/j.jaci.2013.10.045
PubMed: 24332264
05/2014

Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML.
Chaturvedi A and Araujo Cruz MM and Jyotsana N and Sharma A and Yun H and Görlich K and Wichmann M and Schwarzer A and Preller M and Thol F and Meyer J and Haemmerle R and Struys EA and Jansen EE and Modlich U and Li Z and Sly LM and Geffers R and Lindner R and Manstein DJ
DOI: 10.1182/blood-2013-03-491571
PubMed: 23954893
10/2013

Generation and characterization of murine alternatively activated macrophages.
Weisser SB and McLarren KW and Kuroda E and Sly LM
DOI: 10.1007/978-1-62703-128-8_14
PubMed: 23179835
2013

Depletion and reconstitution of macrophages in mice.
Weisser SB and van Rooijen N and Sly LM
DOI: 10.3791/4105
PubMed: 22871793
2012

SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitis.
Weisser SB and Brugger HK and Voglmaier NS and McLarren KW and van Rooijen N and Sly LM
DOI: 10.1189/jlb.0311124
PubMed: 21685246
09/2011

A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation.
Ho VW and Leung K and Hsu A and Luk B and Lai J and Shen SY and Minchinton AI and Waterhouse D and Bally MB and Lin W and Nelson BH and Sly LM and Krystal G
DOI: 10.1158/0008-5472.can-10-3973
PubMed: 21673053
07/2011

SHIP-deficient mice develop spontaneous intestinal inflammation and arginase-dependent fibrosis.
McLarren KW and Cole AE and Weisser SB and Voglmaier NS and Conlin VS and Jacobson K and Popescu O and Boucher JL and Sly LM
DOI: 10.1016/j.ajpath.2011.03.018
PubMed: 21640975
07/2011

Alternative activation of macrophages by IL-4 requires SHIP degradation.
Weisser SB and McLarren KW and Voglmaier N and van Netten-Thomas CJ and Antov A and Flavell RA and Sly LM
DOI: 10.1002/eji.201041105
PubMed: 21469115
06/2011

SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.
Kuroda E and Antignano F and Ho VW and Hughes MR and Ruschmann J and Lam V and Kawakami T and Kerr WG and McNagny KM and Sly LM and Krystal G
DOI: 10.4049/jimmunol.1002778
PubMed: 21131429
01/2011

Tyrosine phosphorylation of SHIP promotes its proteasomal degradation.
Ruschmann J and Ho V and Antignano F and Kuroda E and Lam V and Ibaraki M and Snyder K and Kim C and Flavell RA and Kawakami T and Sly L and Turhan AG and Krystal G
DOI: 10.1016/j.exphem.2010.03.010
PubMed: 20304029
05/2010

The p110a and p110ß isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells.
Ivison SM and Khan MA and Graham NR and Shobab LA and Yao Y and Kifayet A and Sly LM and Steiner TS
DOI: 10.1155/2010/652098
PubMed: 20953381
2010

Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal.
Heuser M and Sly LM and Argiropoulos B and Kuchenbauer F and Lai C and Weng A and Leung M and Lin G and Brookes C and Fung S and Valk PJ and Delwel R and Löwenberg B and Krystal G and Humphries RK
DOI: 10.1182/blood-2009-06-227603
PubMed: 19667399
11/2009

SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils.
Kuroda E and Ho V and Ruschmann J and Antignano F and Hamilton M and Rauh MJ and Antov A and Flavell RA and Sly LM and Krystal G
DOI: 10.4049/jimmunol.0900864
PubMed: 19710468
09/2009

SHIP regulates the reciprocal development of T regulatory and Th17 cells.
Locke NR and Patterson SJ and Hamilton MJ and Sly LM and Krystal G and Levings MK
DOI: 10.4049/jimmunol.0803749
PubMed: 19542365
07/2009

SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.
Sly LM and Hamilton MJ and Kuroda E and Ho VW and Antignano FL and Omeis SL and van Netten-Thomas CJ and Wong D and Brugger HK and Williams O and Feldman ME and Houseman BT and Fiedler D and Shokat KM and Krystal G
DOI: 10.1182/blood-2008-06-166082
PubMed: 19139077
03/2009

Derivation and characterization of murine alternatively activated (M2) macrophages.
Ho VW and Sly LM
DOI: 10.1007/978-1-59745-396-7_12
PubMed: 19347318
2009

IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species.
Sly LM and Kalesnikoff J and Lam V and Wong D and Song C and Omeis S and Chan K and Lee CW and Siraganian RP and Rivera J and Krystal G
DOI: 10.4049/jimmunol.181.6.3850
PubMed: 18768839
09/2008

The inositol phosphatase SHIP controls Salmonella enterica serovar Typhimurium infection in vivo.
Bishop JL and Sly LM and Krystal G and Finlay BB
DOI: 10.1128/iai.01596-07
PubMed: 18426884
07/2008

Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.
Argiropoulos B and Palmqvist L and Yung E and Kuchenbauer F and Heuser M and Sly LM and Wan A and Krystal G and Humphries RK
DOI: 10.1016/j.exphem.2008.02.011
PubMed: 18375036
07/2008

Monocyte p110alpha phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production.
Lee JS and Nauseef WM and Moeenrezakhanlou A and Sly LM and Noubir S and Leidal KG and Schlomann JM and Krystal G and Reiner NE
DOI: 10.1189/jlb.0906564
PubMed: 17369495
06/2007

Re: the terminology issue for myeloid-derived suppressor cells.
Krystal G and Sly L and Antignano F and Ho V and Ruschmann J and Hamilton M
DOI: 10.1158/0008-5472.can-07-0211
PubMed: 17440115
04/2007

The role of SHIP in macrophages.
Sly LM and Ho V and Antignano F and Ruschmann J and Hamilton M and Lam V and Rauh MJ and Krystal G
DOI: 10.2741/2276
PubMed: 17485263
2007

The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia.
Palmqvist L and Argiropoulos B and Pineault N and Abramovich C and Sly LM and Krystal G and Wan A and Humphries RK
DOI: 10.1182/blood-2005-12-007005
PubMed: 16861351
08/2006

SHIP represses the generation of alternatively activated macrophages.
Rauh MJ and Ho V and Pereira C and Sham A and Sly LM and Lam V and Huxham L and Minchinton AI and Mui A and Krystal G
DOI: 10.1016/j.immuni.2005.09.003
PubMed: 16226502
10/2005

The role of SHIP1 in macrophage programming and activation.
Rauh MJ and Sly LM and Kalesnikoff J and Hughes MR and Cao LP and Lam V and Krystal G
PubMed: 15494015
11/2004

LPS-induced upregulation of SHIP is essential for endotoxin tolerance.
Sly LM and Rauh MJ and Kalesnikoff J and Song CH and Krystal G
DOI: 10.1016/j.immuni.2004.07.010
PubMed: 15308103
08/2004

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 and Rauh MJ and Kalesnikoff J and Büchse T and Krystal G
DOI: 10.1016/j.exphem.2003.09.011
PubMed: 14662322
12/2003

The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2.
López M and Sly LM and Luu Y and Young D and Cooper H and Reiner NE
DOI: 10.4049/jimmunol.170.5.2409
PubMed: 12594264
03/2003

Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages.
Rauh MJ and Kalesnikoff J and Hughes M and Sly L and Lam V and Krystal G
PubMed: 12546703
02/2003

Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1.
Sly LM and Hingley-Wilson SM and Reiner NE and McMaster WR
DOI: 10.4049/jimmunol.170.1.430
PubMed: 12496428
01/2003

The role of SHIP in cytokine-induced signaling.
Kalesnikoff J and Sly LM and Hughes MR and Büchse T and Rauh MJ and Cao LP and Lam V and Mui A and Huber M and Krystal G
PubMed: 12692707
2003

Salmonella enterica serovar Typhimurium periplasmic superoxide dismutases SodCI and SodCII are required for protection against the phagocyte oxidative burst.
Sly LM and Guiney DG and Reiner NE
DOI: 10.1128/iai.70.9.5312-5315.2002
PubMed: 12183590
09/2002

1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase.
Sly LM and Lopez M and Nauseef WM and Reiner NE
DOI: 10.1074/jbc.m102876200
PubMed: 11461902
09/2001

1alpha,25-dihydroxyvitamin D(3)-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex.
Hmama Z and Nandan D and Sly L and Knutson KL and Herrera-Velit P and Reiner NE
DOI: 10.1084/jem.190.11.1583
PubMed: 10587349
12/1999

Reconstitution of glucose uptake and chemotaxis in Pseudomonas aeruginosa glucose transport defective mutants.
Sly LM and Worobec EA and Perkins RE and Phibbs PV
PubMed: 8306210
11/1993

Research

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

Lisa Kozicky
Susan Menzies, Lab Manager/Research Assistant Technician
Mahdis Monajemi, Doctoral Student
Yvonne Pang, Masters Student
Jean Sauve
Chris Tang, Directed Studies Student