The transition from inflammation to resolution is critical for the restoration of tissue function following injury or infection, and tissue resident macrophages (TRM) are key immune effectors of both the initiation and resolution phases of inflammation in vivo. TRM promote inflammation by producing cytokines that recruit neutrophils (PMN) and other leukocytes into the damaged tissue. TRM also promote the resolution of inflammation and return to homeostasis by clearing apoptotic cell infiltrates and by producing anti-inflammatory cytokines and growth factors. This dual functionality is a defining property of macrophages, and thus understanding the molecular and cellular events that trigger these TRM states during inflammation holds great therapeutic promise. The phagocytic clearance of apoptotic cells (efferocytosis) is known to shift macrophages toward an anti-inflammatory state, and it is thought that the efferocytosis of infiltrating PMN by macrophages contributes to the shif from inflammation to resolution vivo. However, the mechanisms of efferocytosis-driven resolution in vivo are not well understood. We have found that the adenosine-generating ecto-enzyme CD73 is highly expressed on murine lung and peritoneal TRM and that it is required for the adenosine-mediated anti- inflammatory effects of apoptotic cells on macrophages in vitro and during inflammation in vivo. Our results reveal a previously unknown and critical role for CD73 in controlling inflammatory responses of macrophages during efferocytosis. Here we propose to define the mechanisms whereby apoptotic cells induce a CD73- dependent anti-inflammatory program in macrophages and to investigate the role of CD73 on TRM in regulating the transition from inflammation to resolution during inflammation in vivo.
In Aim 1 we will dissect the mechanisms of CD73-dependent suppression of inflammatory cytokine production by apoptotic cells in vitro.
In Aim 2, we will determine how CD73 links efferocytosis to the resolution of pulmonary and peritoneal inflammation and investigate the molecular basis whereby efferocytosis drives a pro-resolution program in TRM. We believe these studies will produce novel mechanistic insights into an important but poorly understood aspect of inflammation that will aid in developing new approaches to study and control tissue damage during acute and chronic inflammatory diseases.
Improper resolution of inflammation is increasingly being appreciated as a cause and effect of many human diseases. In tissues, macrophages are central regulators of tissue health and immunity. The goal of this research project is to identify extrinsic signals, particularly those delivered by dying cells, that stimulate macrophages to inhibit inflammation and promote resolution and wound healing.
|Murphy, Patrick S; Wang, Jing; Bhagwat, Samir P et al. (2017) CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages. Cell Death Differ 24:559-570|
|Zent, Clive S; Elliott, Michael R (2017) Maxed out macs: physiologic cell clearance as a function of macrophage phagocytic capacity. FEBS J 284:1021-1039|
|Elliott, Michael R; Koster, Kyle M; Murphy, Patrick S (2017) Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses. J Immunol 198:1387-1394|
|Elliott, Michael R; Ravichandran, Kodi S (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38:147-60|