This application seeks to study a subpopulation of activated macrophages that we've identified with potent immunoregulatory activity. We will determine if we can exploit these regulatory macrophages (R-Mf) to develop a novel class of anti-inflammatory therapeutics.
In Aim 1, we will characterize regulatory macrophages, and identify a panel of R-Mf-specific biomarkers to develop a """"""""signature"""""""" for these cells. These biomarkers will be used to determine the various """"""""reprogramming"""""""" signals that can give rise to regulatory macrophages and they will enable the identification of these cells in tissue during disease. We propose that the depletion or induction of R-Mf represent new approaches to treat diseases.
In Aim 2, we will examine the conversion of classically activated macrophages (Ca- Mf) to regulatory macrophages. We propose that Ca-Mf can control their own activation state by secreting ATP and rapidly converting it to adenosine. Adenosine induces a regulatory macrophage phenotype. In the absence of this conversion, macrophage activation progresses uncontrolled, leading to inflammatory pathology. This represents a new paradigm in (controlling) macrophage activation. We will determine the role that macrophage ectoenzymes, CD39 and CD73, play in promoting the conversion of ATP to adenosine by engineering macrophages to overexpress or lack these ectoenzymes. The biomarkers developed in Aim 1 will help us to identify the induction of regulatory macrophages following their exposure to adenosine.
In Aim 3, we will manipulate macrophages to improve human health. We will induce the formation of R-Mf and determine whether the reversal of disease pathology correlates with the induction of regulatory macrophages. We will utilize the """"""""biomarkers"""""""" developed in Aim 1 to identify the persistence of R-Mf in tissue during the process of disease resolution. We will generate R-Mf by either adding exogenous 'reprogramming'signals (Aim 1) or by promoting the conversion of ATP to adenosine (Aim 2). The core hypothesis to be tested in these studies is that macrophage physiology can be reliably and predictably manipulated, and that R-Mf can be exploited to modify immune responses and affect disease outcomes. By inducing regulatory macrophages we can prevent or reverse autoimmune pathologies. By deleting regulatory macrophages we may enhance immunity.

Public Health Relevance

In this application, we propose to identify and characterize a novel population of macrophages, called regulatory macrophages (R-Mf). We will identify a panel of biomarkers on these cells and determine whether the induction of these potent immunoregulatory cells can prevent autoimmune inflammatory diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland College Park
Anatomy/Cell Biology
Earth Sciences/Resources
College Park
United States
Zip Code
Martins, Tassiane Assiria Fontes; Barbosa, Vitor Silva; Almeida, Gregório Guilherme et al. (2018) Monocyte subpopulations as important biomarkers of resistence and susceptibility during experimental infection with Leishmania (Leishmania) major. Biomed Pharmacother 107:1530-1539
Hamidzadeh, Kajal; Christensen, Stephen M; Dalby, Elizabeth et al. (2017) Macrophages and the Recovery from Acute and Chronic Inflammation. Annu Rev Physiol 79:567-592
Suresh, Rahul; Chandrasekaran, Prabha; Sutterwala, Fayyaz S et al. (2016) Complement-mediated 'bystander' damage initiates host NLRP3 inflammasome activation. J Cell Sci 129:1928-39
Cohen, Tatiana V; Many, Gina M; Fleming, Bryan D et al. (2015) Upregulated IL-1? in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages. Skelet Muscle 5:24
Sousa, Louisa M A; Carneiro, Matheus B H; Dos Santos, Liliane M et al. (2015) IL-18 contributes to susceptibility to Leishmania amazonensis infection by macrophage-independent mechanisms. Cytokine 74:327-30
Fleming, Bryan D; Chandrasekaran, Prabha; Dillon, Laura A L et al. (2015) The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling. J Leukoc Biol 98:395-407
Dillon, Laura A L; Okrah, Kwame; Hughitt, V Keith et al. (2015) Transcriptomic profiling of gene expression and RNA processing during Leishmania major differentiation. Nucleic Acids Res 43:6799-813
Cohen, Heather B; Ward, Amanda; Hamidzadeh, Kajal et al. (2015) IFN-? Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response. J Immunol 195:3828-37
Sousa, L M A; Carneiro, M B H; Resende, M E et al. (2014) Neutrophils have a protective role during early stages of Leishmania amazonensis infection in BALB/c mice. Parasite Immunol 36:13-31
Cohen, Heather B; Mosser, David M (2014) Cardiac macrophages: how to mend a broken heart. Immunity 40:3-5

Showing the most recent 10 out of 14 publications