Investigating the immunosuppressive capacity of myeloid cells during the resolution of lung inflammation

In the normal course of inflammation, as the infectious agent is cleared, macrophages of a pro-resolving and anti-inflammatory nature appear in the tissue, to reduce inflammation, clear apoptotic cells and promote tissue recovery. Whether these cells are re-programmed resident cells or differentiated from infiltrating precursors is not fully understood, but they are thought to be induced by the prolonged presence of inflammatory stimuli such as cytokines, DAMPs and PAMPs and by changes induced by phagocytosis of apoptotic neutrophils. Recent data suggests that these cells bestow on the tissue a state of adapted homeostasis such that the local immune system will respond differently to future inflammatory insult.
Myeloid cells are extremely plastic and the tissue environment has a strong influence on their phenotype. It is therefore important to understand the role that myeloid cells play during the resolution of inflammation in different organs and how these cells affect the local immune system following antigenic challenge. Here we will focus on the lung, a mucosal site in which the ability to robustly fight invading pathogens must be balanced with maintaining healthy homeostasis. Defects in the process of resolution after an inflammatory insult could contribute to chronic inflammation, however a resolving state must also be balanced with the need to resist further infection, and the resolution process has been proposed to increase susceptibility to bacterial lung infections after a viral infection.
Macrophage responses become dysfunctional in aged animals, in a process which appears to be due to changes in the tissue environment rather than being intrinsic to the cells or cellular progenitors. It is not known how the ability of myeloid cells to function in the resolution of inflammation is affected by aging. A better understanding of how age impacts the resolving role of myeloid cells is important, to understand chronic inflammation and susceptibility to infection in the elderly.
Hypothesis
We believe that resolving inflammatory insult in the lung will alter the phenotype of the mononuclear phagocytes present and lead to a state of altered homoeostasis which will impact the immune response to future immunological challenge.
Experimental plan
The phenotype of the myeloid cells in the lung after challenge with a simple, resolving inflammatory model will be investigated in both young and aged mice. The potential for the post-resolution immune system in the lung to impact the magnitude of the response to a future immunological challenge will be tested. In addition, the phenotype of myeloid cells in the human lung during chronic inflammation will be investigated to understand whether any of the mechanisms identified in the murine lung model are applicable to chronic inflammation in the human lung.
Project aims
i. Characterise the myeloid cells present during resolving lung inflammation
ii. Study the function of myeloid cells during resolving lung inflammation in aged mice
iii. Investigate the potential for inflammation in the post-resolution lung
iv. Characterise the myeloid cells present in human lung
These studies will involve studying the resolution phase of sterile lung inflammation in the mouse.