Cell biology of the mononuclear phagocyte system with relation to inflammation, innate and adaptive immunity and maintenance of, or return to, normal tissue homeostasis.
Our group has four major, interacting, areas of interest, addressing, in general, the initiation, progression and in particular, resolution and mediator control of the inflammatory process, extending from the biochemical, molecular and cellular levels to animal systems and patient investigation.
One emphasis is represented by our interest in cell death and particularly, the role of apoptotic cell recognition and removal in immunologic processes. Surface structures on apoptotic cells (especially phospholipid species) are recognized by mononuclear phagocytes, dendritic cells and near-neighbor tissue cells) and contribute to processes of tissue homeostasis (cell removal and replacement) and remodeling, as well as in resolution and suppression of inflammation and modulation of adaptive immunity. These studies relate importantly to the pathogenesis of interstitial lung diseases (ILDs) and COPD as well as to normal repair after acute lung injury and inflammation (ALI). Animal and in vitro models for these processes are an important element of our investigative arsenal and experiments extend from, and to, human physiology, pathology and clinical investigation.
A unique form of phagocytosis appears responsible for removal of apoptotic cell and tissue debris from tissues. We have named this “efferocytosis” (from “effero” – to carry to the grave, to bury). It is highly conserved within all metazoa, significantly precedes (in evolutionary terms) “classic” phagocytosis driven by Fc or complement receptor ligation and can be carried out to various levels of efficiency in many mammalian cell types. Signaling, mechanisms, consequences and relation to innate, adaptive and auto-immunity represent a second research focus.
Innate immunity is mediated by groups of soluble or cell surface ligands for pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs). It is now apparent that recognition of apoptotic or necrotic cells and cell debris shows significant similarities and consequences resulting in a delicate balance between anti- and pro-inflammatory responses and subsequent adaptive immunity.
The mononuclear phagocyte lineages (monocytes, macrophages and dendritic cells) represent an increasing focus of attention in our research efforts – extending to their different origins, localization in the tissues, adaptation to their local environment and myriad functions in normal tissue homeostasis, host defense and essential participation in the innate and adaptive immune systems. Importantly these studies increasingly address similarities and differences between the mononuclear phagocytes of mouse and human, especially in within the respiratory tract.
Trainees working in our group take on projects in all these areas from basic cell biology and biochemistry to animal models and translational studies leading into the clinic.