Pieter J.M. Leenen, PhD

Leenen51x53px Associate Professor,
 Laboratory Autoimmune Diseases,
 Department of Immunology

 Email contact: p.leenen@erasmusmc.nl

 Myelomonocytic Cells in Inflammation Research Group (AIP)

Central theme in our research group is the developmental biology of myelomonocytic cells in steady state as well as in diseases where they are aberrant and associated with pathological conditions.

Myelomonocytic cells comprise macrophages and dendritic cells in their various forms as well as granulocytes and their common precursors. They are present in virtually all tissues and involved in many physiological processes. By virtue of a wide array of sensing receptors, they function as sentinel cells to alert host defenses when homeostasis is disturbed. Depending on their state of development and activation, myelomonocytic cells also have important effector functions, for instance in combatting microbial infection, or regulating inflammatory and immune responses. In line with the diverse functions of myelomonocytic cells, their involvement and (mal)function has been shown in a wide variety of diseases, including metabolic and autoimmune diseases such as type 1 and type 2 diabetes, atherosclerosis, obesity, cancer and psychiatric diseases. In particular the inflammatory nature of myelomonocytic cells in these conditions underlies many of the pathological signs and symptoms.

Generation of functional diversity of macrophages occurs in particular at the level of post-monocytic cells in the peripheral tissues. Environmental cues stimulate different gene expression patterns, with related functional consequences, which are generically categorized as M1 / classic activation and M2 / alternative activation. Multiple intermediate and additional activation stages exist, however. Importantly, in our previous studies we found that environmental conditions not only affect mature cells in peripheral tissues but also alter bone marrow precursors in their development and subsequent responses to peripheral triggers. These findings form the basis of our current working hypothesis.

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Current research lines include the role of myelomonocytic cells as biomarkers and pathogenic contributors to several diseases, such as diabetes and metabolism-related vascular disease, in bacterial infection and aging. In this, we aim to identify cellular and molecular diagnostic and therapeutic targets related to vascular complications of type 2 diabetes (T2D). Especially, the effect of alterations in lipoprotein(a), high density lipoprotein (HDL) and low density lipoprotein (LDL) in the initiation and development of microvascular dysfunction in T2D patients suffering from proliferative diabetic retinopathy is investigated.  

These topics are studied in animal models as well as in humans and -related in vitro models, in close collaboration with the Immune Regulation Diagnostics (IRD) workgroup, headed by departmental colleague Wim Dik, as well as with national and international colleagues.

 Group members

Pieter J.M. Leenen – Group leader
Adri van Oudenaren – senior technician
Mahnaz Shariatzadeh – PhD student (collaboration with Immune Regulation Diagnostics (IRD) workgroup, Wim Dik)
We regularly host MSc and BSc students from Erasmus MC or other institutions who perform their research internships in our group.

 Selected Publications

(See for all publications Leenen PJ in PubMed)

Shariatzadeh M, Brandt M, Cheng C, ten Berge JCEM, Rothova A, Leenen PJM, Dik W. Three-dimensional tubule formation assay as therapeutic screening model for ocular microvascular disorders.
Eye. 2018; in press. PMID: 29743587.

Stavast CJ, Erkeland SJ, Leenen PJM. 2018. The interplay between critical transcription factors and microRNAs in the control of normal and malignant myelopoiesis. Cancer Lett 427:28-37. PMID: 29673909.

Mourik BC, Leenen PJ, de Knegt GJ, Huizinga R, van der Eerden BC, Wang J, Krois CR, Napoli JL, Bakker-Woudenberg IA, de Steenwinkel JE.
Immunotherapy added to antibiotic treatment reduces relapse of disease in a mouse model of tuberculosis.
Am J Respir Cell Mol Biol 2017; 56:233-41. PMID: 27654457.

Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM, Leenen PJM.
Interactions between type 1 interferons and the Th17 response in tuberculosis: Lessons learned from autoimmune diseases.
Front Immunol 2017; 8:294. PMID: 28424682.

Kannegieter NM, Hesselink DA, Dieterich M, Kraaijeveld R, Rowshani AT, Leenen PJ, Baan CC.
The effect of tacrolimus and mycophenolic acid on CD14+ monocyte activation and function. PLoS One 2017; 12:e0170806. PMID: 28122021.

Drexhage HA, Dik WA, Leenen PJ, Versnel MA.
The immune pathogenesis of type 1 diabetes: not only thinking outside the cell but also outside the islet and out of the box.
Diabetes 2016; 65:2130-3. PMID: 27456621.

Van Beek AA, Hoogerland JA, Belzer C, De Vos P, De Vos WM, Savelkoul HF, Leenen PJ. Interaction of mouse splenocytes and macrophages with bacterial strains in vitro: the effect of age in the immune response.
Benef Microbes 2016; 7:275-87. PMID: 26689225.

Baldeon RL, Weigelt K, de Wit H, Ozcan B, van Oudenaren A, Sempertegui F, Sijbrands E, Grosse L, van Zonneveld AJ, Drexhage HA, Leenen PJM.
Type 2 diabetes monocyte microRNA and mRNA expression: dyslipidemia associates with increased differentiation-related genes but not inflammatory activation.
PLoS One 2015; 10:e0129421. PMID: 26083362.

Baldeon RL, Weigelt K, de Wit H, Ozcan B, van Oudenaren A, Sempertegui F, Sijbrands E, Grosse L, Freire W, Drexhage HA, Leenen PJM.
Decreased serum level of miR-146a as sign of chronic inflammation in type 2 diabetic patients.
PLoS One 2014; 9:e115209. PMID: 25500583.

Riepsaame J, van Oudenaren A, den Broeder BJ, van IJcken WF, Pothof J, Leenen PJM.
MicroRNA-mediated down-regulation of M-CSF receptor contributes to maturation of mouse monocyte-derived dendritic cells.
Front Immunol 2013; 4:353. PMID: 24198819.

Vereyken EJ, Kraaij MD, Baan CC, Rezaee F, Weimar W, Wood KJ, Leenen PJM, Rowshani AT.
A shift towards pro-inflammatory CD16+ monocyte subsets with preserved cytokine production potential after kidney transplantation.
PLoS One 2013; 8:e70152. PMID: 23922945.

Drevets DA, Dillon MJ, Schawang JE, Stoner JA, Leenen PJM.
IFN-gamma triggers CCR2-independent monocyte entry into the brain during systemic infection by virulent Listeria monocytogenes.
Brain Behav Immun 2010; 24:919-29. PMID: 20211719.

Drevets DA, Schawang JE, Mandava VK, Dillon MJ, Leenen PJM.
Severe Listeria monocytogenes infection induces development of monocytes with distinct phenotypic and functional features.
J Immunol 2010; 185:2432-41. PMID: 20631315.

Egeler RM, van Halteren AG, Hogendoorn PC, Laman JD, Leenen PJM.
Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage. Immunol Rev 2010; 234:213-32. PMID: 20193021.

Leenen PJM, Bechan GI, Melis M, den Broeder BJ, Lohler J, Egeler RM.
Heterogeneity in a mouse model of histiocytosis: transformation of Langerin+ dendritic cells, macrophages, and precursors.
J Leukoc Biol 2010; 87:949-58. PMID: 20145199.

Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJM, Liu YJ, Macpherson G, Randolph GJ, Scherberich J, Schmitz J, Shortman K, Sozzani S, Strobl H, Zembala M, Austyn JM, Lutz MB.
Nomenclature of monocytes and dendritic cells in blood.
Blood 2010; 116:74-80. PMID: 20628149.

Loomans CJ, van Haperen R, Duijs JM, Verseyden C, de Crom R, Leenen PJM, Drexhage HA, de Boer HC, de Koning EJ, Rabelink TJ, Staal FJ, van Zonneveld AJ.
Differentiation of bone marrow-derived endothelial progenitor cells is shifted into a proinflammatory phenotype by hyperglycemia.
Mol Med 2009; 15:152-9. PMID: 19295918.

Ribechini E, Leenen PJM, Lutz MB.
Gr-1 antibody induces STAT signaling, macrophage marker expression and abrogation of myeloid-derived suppressor cell activity in BM cells.
Eur J Immunol 2009; 39:3538-51. PMID: 19830733.

Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Leenen PJM. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.
J Immunol 2004; 172:4410-7.

Drevets DA, Dillon MJ, Schawang JS, Van Rooijen N, Ehrchen J, Sunderkotter C, Leenen PJM.
The Ly-6C(high) monocyte subpopulation transports listeria monocytogenes into the brain during systemic infection of mice.
J Immunol 2004; 172:4418-24.

Nikolic T, Bunk M, Drexhage HA, Leenen PJM.
Bone marrow precursors of nonobese diabetic mice develop into defective macrophage-like dendritic cells in vitro.
J Immunol 2004; 173:4342-51.