Filip Swirski, PhD
Instructor in Medicine (Immunologist), Harvard Medical School

Phone: 617-724-6242
Email: fswirski@mgh.harvard.edu

Monocyte heterogeneity

Existence of monocyte subsets in circulation raises the possibility that monocytes are committed for specific function prior to tissue infiltration. Monocytes and their progeny have long been understood as "plastic" cells, capable of adapting to their local environment. Commitment in the circulation is a departure from this paradigm and may reconcile the perhaps contradictory activities attributed to these cells. It is conceivable that the eventual phenotype monocytes acquire in tissue depends on a sequence of ontogenically (cell dictates environment) and environmentally (environment dictates cell) integrated cues and checkpoints. The emerging picture then, positions monocyte subsets and their progeny as active participants in a vast immune regulatory network, rather than as downstream responders of ongoing inflammation. By extension, the circulatory system is a reservoir of functionally distinct components and may be an attractive target for discriminate therapeutic intervention. The primary interest of my lab is to chart the migratory and functional profile of monocytes and their progeny in health and disease. Experiments utilize state-of-the-art animal models, classical cell biology tools, molecular profiling, and recently developed in vivo molecular imaging and therapeutic technologies that interrogate monocyte biology at multiple resolutions, from the whole animal to a single cell. The projects interact closely with local imaging, immunology and cardiovascular groups and with outside collaborators. Currently, we have focused our interests on the role of monocyte subsets in atherosclerosis.

In atherosclerosis

Atherosclerosis is a complex chronic disease and a leading cause of myocardial infarction and stroke. At present, the dominant conceptual approaches to therapy involve manipulation of lipid metabolism and manipulation of inflammatory processes. Targeting inflammatory processes is an attractive option; since the late 1970s, inflammation has shaped our understanding of the disease and several agents that target leukocyte recruitment and retention are currently in preclinical trials.

Monocytes and macrophages are widely regarded as key cellular protagonists of atherosclerosis; not only do they promote disease through release of inflammatory mediators, but also, as lipid-rich foam cells, they become part of the disease's physical bulk. Their inhibition or ablation may seem, at first, as a clear and simple therapeutic objective. Nevertheless, monocytes are integral to the health of the organism; they are motile circulating leukocytes that patrol the vasculature, replenish tissue with macrophages, and respond to injury, infection and various "danger signals". Their indiscriminate targeting would interfere with normal homeostasis and immunity, and is therefore therapeutically nonviable. The discovery that monocytes are comprised of distinct subsets in human, mouse, and other mammals suggests specialization of function, and has stimulated interest in approaches that discriminate between "harmful" and "beneficial" subsets. Our studies test the hypothesis that monocyte subsets participate differentially in atherosclerosis. We aim to identify how differential accumulation of monocyte subsets influences the lesional environment, to modulate monocyte subsets therapeutically and evaluate impact on disease progression, and to profile monocyte subsets in human atherosclerosis.



Publications
Christen T*, Nahrendorf M*, Wildgruber M, Swirski FK, Aikawa E, Waterman P, Shimizu K, Weissleder R, Libby P
Molecular Imaging of Innate Immune Cell Function in Transplant Rejection.
Circulation. 2009;119(14):1925-32 - PMID: 19332470 - PMCID: PMC2676889
Swirski FK, Weissleder R, Pittet MJ
Heterogeneous In Vivo Behavior of Monocyte Subsets in Atherosclerosis.
Arterioscler Thromb Vasc Biol. 2009;:ePub - PMID: 19372462
Leimgruber A, Berger C, Cortez-Retamozo V, Etzrodt M, Newton A, Waterman P, Figueiredo JL, Kohler R, Elpek N, Mempel TR, Swirski FK, Nahrendorf M, Weissleder R, Pittet MJ
Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle
Neoplasia. 2009;11(5):459-468 - PMID: 19412430 - PMCID: PMC2672160 - Cover
Wildgruber M, Lee H, Chudnovskiy A, Yoon T, Etzrodt M, Pittet M, Nahrendorf M, Croce K, Libby P, Weissleder R, Swirski F
Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors.
PLoS ONE. 2009;4(5):e5663 - PMID: 19461894 - PMCID: PMC2680949
Nahrendorf M, Sosnovik D, French B, Swirski FK, Bengel F, Sadeghi MM, Lindner JR, Wu JC, Kraitchman DL, Fayad ZA, Sinusas AJ
Multimodality Cardiovascular Molecular Imaging, Part II
Circ Cardiovasc Imaging. 2009;2:56-70
Cortez-Retamozo V, Swirski FK, Waterman P, Yuan H, Figueiredo JL, Newton AP, Upadhyay R, Vinegoni C, Kohler R, Blois J, Smith A, Nahrendorf M, Josephson L, Weissleder R, Pittet MJ
Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation
J Clin Invest. 2008;:ePub - PMID: 18989378 - PMCID: PMC2579705
Kircher M, Grimm J, Swirski FK, Libby P, Gerszten R, Allport J, Weissleder R
Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions.
Circulation. 2008;117:388-395 - PMID: 18172031
Nahrendorf M, Sosnovik D, Chen JW, Panizzi P, Figueiredo JL, Aikawa E, Libby P, Swirski FK, Weissleder R
Activatable Magnetic Resonance Imaging Agent Reports Myeloperoxidase Activity in Healing Infarcts and Noninvasively Detects the Antiinflammatory Effects of Atorvastatin on Ischemia-Reperfusion Injury.
Circulation. 2008;117(9):1153-60 - PMID: 18268141 - PMCID: PMC2673051
Nahrendorf M, Zhang H, Hembrador S, Panizzi P, Sosnovik D, Aikawa E, Libby P, Swirski F, Weissleder R.
Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis
Circulation. 2008;117:379-387 - PMID: 18158358 - PMCID: PMC2663426
Libby P, Nahrendorf M, Pittet MJ, Swirski FK
Diversity of denizens of the atherosclerotic plaque: not all monocytes are created equal.
Circulation. 2008;117(25):3168-70 - PMID: 18574058
Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ
Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata
J Clin Invest. 2007;117(1):195-205 - PMID: 17200719 - PMCID: PMC1716211
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ
The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
J Exp Med. 2007;204(12):3037-47 - PMID: 18025128 - PMCID: PMC2118517
Aikawa E, Nahrendorf M, Figueiredo JL, Swirski F, Shtatland T, Kohler RH, Jaffer F, Aikawa M, Weissleder R.
Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo.
Circulation. 2007;116(24):2841-50 - PMID: 18040026
Nahrendorf M, Sosnovik D, Waterman P, Swirski F, Pande A, Aikawa E, Figueiredo JL, Pittet M, Weissleder R.
Dual channel optical tomographic imaging of leukocyte recruitment and protease activity in the healing myocardial infarct
Circ Res. 2007;100:1218-1225 - PMID: 17379832
Pittet M, Grimm J, Berger C, Tamura T, Wojtkiewicz G, Nahrendorf M, Romero P, Swirski F, Weissleder R.
In vivo imaging of T cell delivery to tumors after adoptive transfer therapy
P Natl Acad Sci U S A. 2007;104:12457-12461 - PMID: 17640914 - PMCID: PMC1941490
Johnson J, Swirski F, Gajewska B, Wiley R, Fattouh R, Pacitto S, Wong J, Stampfli M, Jordana M
Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes.
Am J Physiol Lung Cell Mol Physiol. 2007;293:L730-9 - PMID: 17586699
Swirski FK, Berger CR, Figueiredo JL, Mempel TR, von Andrian UH, Pittet MJ, Weissleder R
A near-infrared cell tracker reagent for multiscopic in vivo imaging and quantification of leukocyte immune responses.
PLoS ONE. 2007;2(10):e1075 - PMID: 17957257 - PMCID: PMC2034600
Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P, Weissleder R
Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease.
P Natl Acad Sci U S A. 2006;103(27):10340-5 - PMID: 16801531 - PMCID: PMC1502459
Alvarez D, Swirski F, Yang T, Fattouh R, Croitoru K, Bramson J, Stampfli M, Jordana M
Inhalation tolerance is induced selectively in thoracic lymph nodes but executed pervasively at distant mucosal and nonmucosal tissues.
J Immunol. 2006;176(4):2568-80 - PMID: 16456019
Swirski F, D'Sa A, Kianpour S, Inman M, Stampfli M
Prolonged ovalbumin exposure attenuates airway hyperresponsiveness and T cell function in mice.
Int Arch Allergy Immunol. 2006;141(2):130-40 - PMID: 16864992
Pittet M, Swirski F, Reynolds F, Josephson L, Weissleder R.
Labeling of immune cells for in vivo imaging using magnetofluorescent nanoparticles
Nat Protocols. 2006;1(1):73-79
Gajewska B, Tafuri A, Swirski F, Walker T, Johnson J, Shea T, Shahinian A, Goncharova S, Mak T, Stampfli M, Jordana M
B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance.
J Immunol. 2005;174(5):3000-5 - PMID: 15728513
Johnson J, Wiley R, Fattouh R, Swirski F, Gajewska B, Coyle A, Gutierrez-Ramos J, Ellis R, Inman M, Jordana M
Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling.
Am J Respir Crit Care Med. 2004;169(3):378-85 - PMID: 14597485
Swirski F, Gajewska B, Robbins C, D'Sa A, Johnson J, Pouladi M, Inman M, Stampfli M
Concomitant airway expression of granulocyte-macrophage colony-stimulating factor and decorin, a natural inhibitor of transforming growth factor-beta, breaks established inhalation tolerance.
Eur J Immunol. 2004;34(9):2375-86 - PMID: 15307170
Pouladi M, Robbins C, Swirski F, Cundall M, McKenzie A, Jordana M, Shapiro S, Stampfli M
Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice.
Am J Respir Cell Mol Biol. 2004;30(1):84-90 - PMID: 12842850
Robbins C, Dawe D, Goncharova S, Pouladi M, Drannik A, Swirski F, Cox G, Stampfli M
Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness.
Am J Respir Cell Mol Biol. 2004;30(2):202-11 - PMID: 12920055
Ritz S, Cundall M, Gajewska B, Swirski F, Wiley R, Alvarez D, Coyle A, Stampfli M, Jordana M
The lung cytokine microenvironment influences molecular events in the lymph nodes during Th1 and Th2 respiratory mucosal sensitization to antigen in vivo.
Clin Exp Immunol. 2004;138(2):213-20 - PMID: 15498029 - PMCID: PMC1809215
Swirski F, Sajic D, Robbins C, Gajewska B, Jordana M, Stampfli M
Chronic exposure to innocuous antigen in sensitized mice leads to suppressed airway eosinophilia that is reversed by granulocyte macrophage colony-stimulating factor.
J Immunol. 2002;169:3499-506 - PMID: 12244139
Swirski F, Gajewska B, Alvarez D, Ritz S, Cundall M, Cates E, Coyle A, Gutierrez-Ramos J, Inman M, Jordana M, Stampfli M
Inhalation of a harmless antigen (ovalbumin) elicits immune activation but divergent immunoglobulin and cytokine activities in mice.
Clin Exp Allergy. 2002;32:411-21 - PMID: 11940072
Gajewska B, Swirski F, Alvarez D, Ritz S, Goncharova S, Cundall M, Snider D, Coyle A, Gutierrez-Ramos J, Stampfli M, Jordana M
Temporal-spatial analysis of the immune response in a murine model of ovalbumin-induced airways inflammation.
Am J Respir Cell Mol Biol. 2001;25:326-34 - PMID: 11588010
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