Innate response activator (IRA) B cells in infection
Sepsis, a life-threatening condition, is characterized by whole-body inflammation to overwhelming infection. Over the last thrity years, the incidence of sepsis has risen, indicating a need for a better understanding of its complex pathophysiology. The condition presents an immunological conundrum. On the one hand, development of severe sepsis results from a failure of the immune system to control infection, but on the other, responding immune cells that can eliminate the infection inflict damage to the host by contributing to complications such as endothelial leakage and septic shock. A major therapeutic goal, then, is to strike a balance between controlling infection and controlling inflammation. We recently described a cell population that protects against sepsis. The cell, named innate response activator (IRA), belongs to the B cell family, derives from B1a B cells via MyD88, and produces GM-CSF, which is a multifaceted growth factor that contributes to hematopoiesis and myeloid cell function. Currently, our studies focus on understanding the biology of IRA-B cells in more detail. We focus on the cell’s development and effector function.
Monocytes and macrophages are essential to atherosclerosis. As disease worsens, the number of circulating monocytes rises whereas in models with monocyte depletion atherosclerosis neither develops nor evolves. In the steady state, hematopoietic stem and progenitor cells (HSPC) give rise to monocytes in the bone marrow. These marrow-derived, medullary monocytes (mMos) mobilize from the bone marrow, circulate, accumulate in tissue, and differentiate to macrophages or dendritic cells. During atherosclerosis, HSPCs also mobilize from their bone marrow niches and preferentially seed the spleen. As a result, the spleen becomes hematopoietic and produces monocytes, neutrophils and other cells that intravasate, circulate, and accumulate in atheromata. The atheromata, recent studies show, contains a highly heterogenous population of macrophages and dendritic cells. In this project we are testing the hypothesis that medullary and extramedullary hematopoiesis are distinct processes that contribute to atherosclerosis differentially. We will pay particular attention to the medullary and extramedullary production of monocytes, as these are the central culprits in atherosclerosis. Extramedullary monocytes (eMos), we propose, arise in a “hostile” extramedullary niche, differ from monocytes that originiate in the “protected” bone marrow niche, and differentiate to distinct macrophages. eMos-derived lesional macrophages are imprinted with an extramedullary signature and contribute to atherosclerosis in distinct and consequential ways.
Monocytes are heterogeneous in both human and mouse. One monocyte subset (Ly-6Chi in mouse; CD16- in human) expands in hypercholesterolemic animals and selectively gives rise to macrophages in atheromata. A different subset (Ly-6Clo in mouse; CD16+ in human) attenuates inflammation and promotes angiogenesis and granulation tissue formation in experimental models of tissue injury, but its role in atherosclerosis is unknown. These cells' contradistinctive properties suggest commitment for specific function prior to infiltrating tissue. Such commitment argues for discriminate targeting of deleterious subsets while sparing host defense and repair mechanisms. In this project we are testing the hypothesis that monocyte subsets contribute differentially to atherogenesis and can be targeted selectively to image and treat disease progression. In addition to advancing our understanding of atherosclerosis, the ability to target monocyte subsets would allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications such as myocardial infarction or stroke.