During infection and inflammation, monocytes are recruited from the circulation to inflamed tissues by chemokines where they are activated by multiple inflammatory mediators and matrix components. As the initiating agents are eliminated end inflammation wanes, the monocytes are no longer necessary and must be removed from the tissues to resolve inflammation. Failure in this removal process may become pathogenic, and many chronic inflammatory conditions, including rheumatoid and experimentally-induced arthritis and destructive periodontal disease are associated with the persistent accumulation of inflammatory cells. Therefore, understanding the mechanisms which control normal monocyte deletion and potential aberrancies may underlie the development of strategies for modulating chronic inflammatory pathology. In this regard, apoptosis which represents a fundamental mechanism for eliminating unwanted cells in the midst of living tissues, may play a role in controlling monocyte accumulation at an inflammatory lesion. In defining the intracellular pathways leading to monocyte death we have demonstrated at least two discrete pathways regulating monocyte life-span involving oxygen intermediates (ROI), protein kinase C (PKC), and Bc1-2. Further unraveling of these dichotomous routes of monocyte apoptosis may not only provide new molecular clues in the apoptotic signaling cascade, but also identify potential targets for regulating this crucial inflammatory process. Extending these studies to animal models has provided exciting new data which define an unique spectrum of cell specific and temporally dependent apoptotic events which are pivotal in the evolution of bacterial cell wall-induced arthritis, and which are consistent with a role for dysregulation of apoptotic pathways in emerging pathogenesis.
