Phagocytic cells, including granulocytes and macrophages play a critical role in inflammatory responses and contribute to the pathogenesis of inflammatory disorders. The activation of inflammatory cells is a complex process whose mechanisms can now be elucidated. These cells respond to chemoattractants generated during humoral or cellular reactions. Directional migration of phagocytic cells requires complex interactions involving adhesion molecules and chemoattractant receptors with their appropriate ligands. At sites of cellular accumulation phagocytes may become further activated to increase their endocytotic, microbicidal, tumoricidal and tissue destructive properties. They also can be desensitized. At sites of inflammation, multiple stimuli are present and there are receptors on phagocytes for multiple mediators. Phagocytic cells exist in various states of activation which are mediated by their exposure to multiple stimuli. The responsiveness of phagocytes at sites of inflammation is clearly relevant to host protection and/or destruction. An important hypothesis of the work herein is that the state of activation of phagocytes is regulated by the interactions of chemoattractant receptors on these cells with multiple inflammatory stimuli. In addition to their own transduction pathways, it is proposed that cross-regulation of cellular signaling pathways modulate the activity of other receptors in a coordinated fashion. Thus, depending on the nature and sequence of stimulation, cells may be either primed, activated or desensitized. This laboratory has developed cellular models of inflammatory cells which are amenable to genetic manipulation and biochemical and biological analysis. Using this model, it has been shown that chemoattractant receptors display different patterns of phosphorylation which have relevance to their biological activities. Moreover, receptors for peptide chemoattractants couple to different G proteins than receptors for lipid chemoattractants; this appears to affect their regulation and cytotoxic potential. Receptor cross-regulation appears to play an important role in priming and desensitization. The experiments proposed in this application examine the mechanisms for priming, activation and desensitization in inflammatory cells by chemoattractant and other receptors which cross regulate each other to modulate inflammatory processes. This work will broaden our understanding of the molecular basis for the protective and destructive properties of phagocytes and will provide useful models for understanding of receptor cross-regulation.
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