Recognition and removal of apoptotic cells is a critically important and highly conserved biologic process that is ?silent? with regard to local tissue responses. We have previously shown that the apoptotic cells induce an active anti-inflammatory response that is mediated in large part by the redistribution of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane and its subsequent recognition by responding phagocytes and other cells. More recently we have shown that PS on the apoptotic cells can also suppress the adaptive immune response. In the lung, as elsewhere in the body, these effects are suggested to mediate the resolution of normal, protective and self-limited inflammatory responses by removing apoptotic inflammatory cells, suppressing the ongoing inflammation while at the same time preventing inappropriate immune reactions. We have also shown that much of the inflammosuppression and immunosuppression initiated by recognition of the PS is mediated through the induction and effects of transforming growth factor beta (TGFa). Nevertheless, despite the information that we and others have gathered on the role of exposed PS, we still do not have an adequate understanding of the mechanisms and particularly, the receptors that recognize and respond to the PS, especially in its ability to drive the suppressive processes. Recently a number of candidate direct ?receptors? for PS have been identified to go along with previously described bridge molecules that bind on the one hand to PS on the apoptotic cells and on the other to receptors on the responding phagocyte. Accordingly, we suggest that the time is now ripe for a concerted approach to determine the receptors and mechanisms underlying the inflammosuppressive and immunosuppressive effects of PS-exposing apoptotic cells. These studies will be carried out in the pulmonary environment and following our usual approach will involve investigations both in vitro and in vivo. The proposal encompasses two specific aims, one on the inflammosuppression and one on immunosuppression, with major emphases on characterizing the role for TGFa and identifying the relevant receptors, first in vitro and then in vivo as well as exploring novel mechanisms by which immune responses in the lung are modulated. Implications and broader objectives of this work are the ability to use the knowledge obtained to deliberately block ongoing inflammatory and/or immunologic reactions in the lung and indeed the proposal includes early studies to explore this potential.
The normal lung is constantly exposed to the external environment and needs to discriminate between relatively harmless exposure and potentially dangerous insults, mounting self-limiting inflammatory reactions and also local immune responses where necessary. Resolution of normal inflammation involves apoptosis of the recruited inflammatory cells, leading both to their removal as well as to stimulation of an active anti- inflammatory response;events driven in part by exposure of phosphatidylserine (PS) on the apoptotic cells. In the first period of this grant we have addressed the role of the PS in suppressing the inflammation and have determined some of the mechanisms involved. However, the receptors that recognize the PS and drive the process have remained elusive. More recently, a number of candidates for this function have been described and we believe it is time to address in detail this crucial step in the process. In addition, we have also found that the PS on apoptotic cells can be immunosuppressive. This raises important questions about their effect on the immunogenicity of pathogens in the lung when in the context of many apoptotic cells, such as during resolution of the inflammation that was initiated as part of the innate immune to the pathogen. Accordingly, we propose also to address the mechanisms by which apoptotic cells and PS inhibit the pulmonary adaptive immune response. The long-term objective will be to develop approaches to manipulate these natural regulatory processes to suppress unwanted ongoing inflammation and to enhance the immunologic responses to pathogens or block those leading to disease - for example in asthma or autoimmunity.
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