MACROPHAGE EMIGRATION FROM THE INFLAMED KIDNEY INTERSTITIUM: REGULATION BY APOPTOTIC CELLS

Inflammation of the kidneys is a serious condition and, even with conventional medical treatment, can lead to kidney scarring and kidney failure such that dialysis or a kidney transplant is required. The macrophage is a white blood cell that plays a key role in inflammatory processes and a body of evidence implicates the macrophage in progressive renal inflammation. Macrophage infiltration in resolving inflammation is transient and evidence suggests that macrophages may leave inflamed sites via the lymphatic system and traffic to lymph nodes. Dying cells are present within inflamed and healing tissues and are an important stimulus for macrophages. Indeed, the ingestion of dying cells by macrophages promotes the generation of anti-inflammatory mediators that facilitate the resolution of inflammation. Our work indicates that the instillation of dying cells into the abdomen directs resident or inflammatory peritoneal macrophages to exit the abdomen and emigrate to the draining lymph nodes. Furthermore, we have evidence implicating a particular receptor on the macrophage in this process. In this proposal we shall determine whether dying cells within the inflamed and healing kidney may similarly direct macrophages to emigrate from the kidney and dissect the underlying mechanism. This work may allow us to generate new ways to dampen down kidney inflammation in patients by promoting the emigration of injurious macrophages from the inflamed kidney.

Macrophages play a prominent role in both glomerular and tubulointerstitial renal inflammation. Persistent macrophage infiltration is associated with a poor clinical outcome in renal patients and the removal of macrophages is a prerequisite for normal tissue healing. Much is known about macrophage recruitment to inflamed sites including the kidney but there is very little data regarding the fate of macrophages in resolving disease. Data from resolving peritonitis indicates that macrophages do not die in situ but traffic to draining lymph nodes - a fate that has been demonstrated in one previous study of glomerulonephritis. Dying apoptotic cells are present throughout the progressive and resolving phases of inflammation and the phagocytic clearance of apoptotic cells is known to exert powerful anti-inflammatory effects upon macrophages. Our recent data indicates that apoptotic cells can drive the emigration of both resident and inflammatory peritoneal macrophages to the draining parathymic lymph nodes thus suggesting an additional important effect of apoptotic cells upon macrophage function. We have also shown that emigrating inflammatory peritoneal macrophages within the draining lymph nodes express the chemokine receptor CCR7 - a key regulator of lymphocyte and dendritic cell trafficking. In this proposal we will use several powerful tools to determine whether apoptotic cells drive macrophage emigration from the ?solid? tubulointerstitium of the kidney during the resolution phase of renal injury: (i) a reversible model of renal obstruction characterised by profound loss of infiltrating interstitial macrophages and apoptosis of accumulated myofibroblasts and (ii) a model of conditional macrophage ablation that facilitates the induction of rapid ?waves of apoptosis? within the tubulointerstitium and (iii) C1q knockout mice that exhibit a well characterised defect in macrophage clearance of apoptotic cells. We will determine the role of chemokines and adhesion molecules in macrophage emigration from the kidney predicting a key role for CCR7, VLA-4 and VCAM-1. This work will explore a new and unchartered area of the ?apoptotic cell/macrophage? interaction and may have important implications for macrophage trafficking in other organs such as the liver and lung.