Leukocyte apoptosis is also a chara

Leukocyte apoptosis is also a characteristic feature of self-limiting inflammation resulting from acute, localized and moderate injury or infection. However, unlike sepsis, apoptotic cells are thought to be beneficial in self-resolving inflammation by helping to reprogram tissue macrophages from a pro-inflammatory to a pro-resolution state (17). Tissue resident macrophages are key immune sentinels and thus are among the first immune cells to respond to tissue damage by producing cytokines that initiate and orchestrate the recruitment of granulocytes from the blood into the tissue (18). Neutrophils typically accumulate in significant numbers within minutes to a few hours depending on the nature and severity of the injury. Once in the tissue, most neutrophils rapidly undergo apoptosis and begin to accumulate as uncleared apoptotic cells. The time at which viable neutrophil numbers are highest in the tissue is often considered the “peak” of a self-limiting inflammatory episode (17). Importantly, the maximum number of uncleared apoptotic neutrophils in the tissue typically coincides with this “peak”, followed by macrophage-mediated efferocytosis and clearance of the neutrophils during the resolution stage (19). Such observations support the theory that efferocytosis of apoptotic neutrophils by resident macrophages is an important immune trigger for the onset of resolution (20, 21). However confirmation of this theory has been hampered by the difficulty in tracking the fate of engulfed endogenous apoptotic cells. Nonetheless, there is abundant evidence that apoptotic cells can suppress macrophage inflammatory responses in vitro and that failure to clear apoptotic cells exacerbates inflammation in vivo, indicating efferocytosis plays a crucial role in modulating the inflammatory response of macrophages (and other phagocytes) to promote resolution (5, 6, 22).