Macrophages have important immune as well as local tissue homeostatic roles, and altered macrophage function is suspected to contribute towards many disease processes including atherosclerosis, metabolic syndrome, and cancer. Macrophages exist in several specialized forms (subsets) that have distinct anatomic locations, cell surface markers, and functions. While circulating monocytes are thought to give rise to these tissue-specific macrophage subsets, the developmental basis for such tissue-specific differentiation is unknown. Previous published work from Dr. Kenneth Murphy's laboratory demonstrated for the first time the requirement for a specific transcription factor (SpiC) for the development of a specific macrophage subset (splenic Red Pulp Macrophage, RPM). The primary homeostatic function of RPMs is to degrade heme and recycle the iron for subsequent erythropoesis. The candidate's work in Dr. Murphy's lab has focused on understanding the regulation and function of SpiC in RPMs. Surprisingly, this work has discovered that SpiC expression is induced by a metabolite of erythrocyte degradation, heme. Further studies uncovered a role for the transcriptional repressor Bach1 in heme mediated regulation of SpiC. These findings demonstrate a role of tissue-specific metabolites in directing macrophage diversity. The goals of this project are to characterize the mechanisms underlying heme-mediated induction of SpiC, uncover the developmental program controlled by SpiC in RPM biology, and investigate the physiological and pathological implications of heme-mediated induction of SpiC. The work proposed here will be carried out in the laboratory of Dr. Kenneth Murphy, who has recently made significant contributions to the area of macrophage and dendritic cell development and function. The candidate is a MD/PhD who has completed residency training in Clinical Pathology and wishes to train further in basic sciences. The long term goal of the candidate is to establish an independent research laboratory investigating the role of macrophages in disease processes.

Public Health Relevance

Macrophages play a critical role in the innate immune system as well as local tissue homeostasis. Different tissues harbor distinct macrophage subsets. Circulating monocytes are thought to differentiate into tissue specific macrophages, but the developmental mechanisms controlling this tissue specific differentiation are not known. The proposed research explores the novel hypothesis that tissue specific metabolites induce na?ve monocytes to differentiate into tissue specific macrophages. This pathway may also have important implications in pathologic states as described in this proposal.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Alam, Md Zahidul; Devalaraja, Samir; Haldar, Malay (2017) The Heme Connection: Linking Erythrocytes and Macrophage Biology. Front Immunol 8:33
Wu, Xiaodi; Briseño, Carlos G; Grajales-Reyes, Gary E et al. (2016) Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate. Proc Natl Acad Sci U S A 113:14775-14780
Briseño, Carlos G; Haldar, Malay; Kretzer, Nicole M et al. (2016) Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells. Cell Rep 15:2462-74
Wu, Xiaodi; Briseño, Carlos G; Durai, Vivek et al. (2016) Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells. J Exp Med 213:2553-2565
Bednarski, Jeffrey J; Pandey, Ruchi; Schulte, Emily et al. (2016) RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals. J Exp Med 213:209-23
Grajales-Reyes, Gary E; Iwata, Arifumi; Albring, Jörn et al. (2015) Batf3 maintains autoactivation of Irf8 for commitment of a CD8?(+) conventional DC clonogenic progenitor. Nat Immunol 16:708-17
Haldar, Malay; Kohyama, Masako; So, Alex Yick-Lun et al. (2014) Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156:1223-1234
Haldar, Malay; Murphy, Kenneth M (2014) Origin, development, and homeostasis of tissue-resident macrophages. Immunol Rev 262:25-35