Research in the Hamerman Lab is focused on understanding the process of inflammation and how it is regulated by specific subsets of myeloid cells. We study monocytes and macrophages, initiators of inflammation, and dendritic cells (DCs), initiators of adaptive immunity. The lab investigates molecular mechanisms by which these cells initiate inflammatory and immune responses after recognition of pathogens, studying both positive and negative regulatory pathways. The goal is to understand how these myeloid cells respond during infection and inflammation, and how this promotes clearance of pathogens and susceptibility to inflammatory and autoimmune disease.
Molecular regulation of innate sensing pathways
Macrophages and DCs recognize pathogens by using a variety of cell surface and intracellular receptors termed pattern recognition receptors, including the family of Toll-like receptors (TLRs). The Hamerman lab studies how signaling through TLRs and other sensing pathways results in appropriate inflammatory responses. The team is particularly interested in proteins that inhibit signaling through pattern recognition receptors, providing an essential check to the inflammatory response. They study several proteins that regulate TLR signaling using biochemical and cellular approaches, and investigate how the functions of these proteins differ between different innate cell types. The lab also uses in vivo models to understand how these signaling pathways contribute to clearance of pathogens, inflammatory challenges, and pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE).
One recent focus of the Hamerman Lab has been on the signaling adaptor BCAP, which is expressed in monocytes, macrophages and DCs as well as in B cells, NK cells and activated/effector T cells. They have shown that BCAP has important regulatory effects on TLR signaling that differ by cell type:
- In macrophages, BCAP inhibits TLR-induced inflammatory cytokine production through activation of PI3-kinase.
- In plasmacytoid DCs, BCAP promotes TLR7/9-induced IFNα production, but does not affect the production of inflammatory cytokines.
The group is now defining the molecular and cellular mechanisms by which BCAP has these differential effects.
The Hamerman Lab has also identified novel proteins that interact with BCAP. One BCAP-interacting protein in particular, the actin regulatory protein Flightless-1, has previously been identified as a regulator of caspase-1 activity. In new work, the Hamerman Lab showed that BCAP and Flightless-1 together inhibit a distinct innate sensing pathway, the NLRP3 and NLRC4 inflammasomes. Future work focuses on how BCAP and Flightless-1 regulate multiple aspects of monocyte, macrophage and DC function, including responses to infection and cell migration, and how they regulate in vivo immune responses in cell-type specific manners, including during bacterial and viral infection and in lupus-like disease.
Regulation of myeloid differentiation during inflammation
The Hamerman Lab also studies the development of cells that participate in innate immune responses, such as monocytes, macrophages, neutrophils and dendritic cells. This process of myelopoiesis occurs in the bone marrow and can respond dynamically to infection and inflammation to produce more cells when needed, in a process called 'emergency myelopoiesis.' The lab is interested in identifying molecular mechanisms that control emergency myelopoiesis and understanding how myeloid cells that develop during inflammation differ from those that develop during homeostasis. Myeloid progenitors express TLRs and can directly respond to these signals to differentiate into monocytes and macrophages.
Work from the Hamerman lab over the last few years has defined how TLR signaling in combination with cytokines promote emergency myelopoiesis in vitro and in vivo, with a focus on TLR7 and type I IFN signaling. More recent work has defined a novel monocyte differentiation pathway that occurs in response to TLR7 and TLR9 signaling in vivo. This pathway causes the differentiation of a novel monocyte-derived cell, the inflammatory hemophagocyte (iHPC).
iHPC efficiently phagocytose red blood cells and thereby cause anemia in a model of TLR7-driven inflammatory disease modeling the human disease Macrophage Activation Syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (HLH). iHPC also differentiate in a TLR7/9-dependent manner in a preclinical model of blood stage malaria that is also associated with severe anemia. These findings suggest there is a common endosomal TLR-driven, inflammatory differentiation pathway for monocytes that cause acute, life threatening cytopenias, including anemia and thrombocytopenia.
Current work in the Hamerman Lab investigates iHPC in both MAS and blood stage malaria in both model systems and primary patient samples. This work aims to identify the signaling pathways downstream of TLR7 and TLR9 that drive iHPC differentiation, the mechanisms by which iHPC phagocytose RBC and platelets, and the phenotype and function of human iHPC.
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