TOLL RECEPTORS IN MACROPHAGE & DENDRITIC CELL ACTIVATION

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DESCRIPTION: (adapted from applicant's abstract) Macrophages normally ingest and kill pathogens in a pro-inflammatory manner that leads to the development of effective immunity, but clear apoptotic cells without stimulating an inflammatory or immune response to self. By contrast, recent data suggest that dendritic cells (DCs) release pro-inflammatory cytokines in response to apoptotic cells. The response to apoptotic cells is normally non-inflammatory and non-immunogenic indicating that the abilities of apoptotic cells to counter pro-inflammatory responses may play a critical and epistatic role in self-tolerance. Perhaps consistent with this notion, apoptotic cells are poorly cleared by macrophages from systemic lupus erythematosus (SLE) patients, can activate macrophages in these patients, and contain within their blebs the nuclear antigens that are recognized by SLE antibodies, which may be factors in disease development. The goals of the application are to address the mechanisms by which apoptotic cells modulate the response of macrophages and DCs to apoptotic cells and inflammatory agonists. The hypothesis is that Toll-like receptors (TLRs) play a critical role in these processes. TLRs are recently identified innate immune receptors that transduce signals in response to lipopolysaccharide (LPS) and other microbial components. TLRs may be important in macrophage down-regulation by apoptotic cells because: 1) apoptotic cells down-regulate macrophage responses to LPS, which signal through TLRs; 2) apoptotic cells and TLRs both regulate macrophage cytokine production; 3) CD14 is important for phagocytosis of apoptotic cells and also enhances TLR signaling; and 4) TLRs are recruited to phagosomes. Aim 1 is the development of reagents for the evaluation of murine TLR expression and function. Aims 2 and 3 uses these reagents to evaluate TLR 2, 4, and 5 expression in macrophages and DCs before and after phagocytosis of apoptotic cells and determines whether apoptotic cells signal through TLRs or modulate the expression and signaling by TLRs.