The inflammatory macrophage: a story of Jekyll and Hyde

Recent investigations have highlighted new roles for the macrophage (Mphi) in the biology of inflammation. Selective depletion of Mphis from inflamed sites has confirmed their predominant role in immune-mediated damage. The components of this injury have been dissected. Mphis mediate death of stromal, parenchymal and other immune cells by engaging the death programme, resulting in apoptosis. In addition, Mphis induce destruction of matrix and extracellular structures both directly and indirectly by inducing stromal cells to release matrix metalloproteinases. However, there is another side to the inflammatory Mphi. Evidence is provided that Mphis at the same sites possess the ability to aid cell proliferation, secrete and stabilize new matrix components and induce resident cells to secrete matrix components themselves. Mphi phagocytosis of apoptotic cells brings about a change from the cell-killing matrix-degrading cell to the matrix-generating cell-proliferating tissue-healing cell. Just as both Mphi types are necessary at the inflamed site, the right balance of these two populations is required for healing and resolution. Evidence of excessive inflammation as a manifestation of impaired phagocytosis of apoptotic cells emphasizes that defects in the transition from one Mphi type to another may account for the uncontrolled excessive inflammation seen in disease. Recent insights into the mechanisms by which apoptotic cells signal the change of function to the Mphi offer the prospect of novel targets for manipulation of Mphis in the inflamed tissue.