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. 2006 Dec 26;103(52):19794-9.
doi: 10.1073/pnas.0609671104. Epub 2006 Dec 13.

"V体育官网" Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Tracie A Seimon  1 , Amrom Obstfeld, Kathryn J Moore, Douglas T Golenbock, Ira Tabas
Affiliations

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Tracie A Seimon et al. Proc Natl Acad Sci U S A. .

Abstract

Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages VSports手机版. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-beta. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical. .

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"VSports在线直播" Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The TLR4 pathway is necessary for SRA-dependent apoptosis of ER-stressed macrophages. (A) Macrophages from WT, Myd88−/−, Tlr2−/−, Tlr4del, or Cd14−/− mice were incubated for 24 h with 0.5 μM thapsigargin (Tg) or thapsigargin plus 50 μg/ml fucoidan (Fuc). The cells then were stained with Alexa 488 annexin-V and propidium iodide and quantified for apoptosis. (B and C) WT or Tlr4del macrophages were incubated for the indicated times with fucoidan, thapsigargin plus fucoidan, or 100 μg/ml acetyl-LDL (Ac-LDL) plus 10 μg/ml compound 58035. Cell lysates then were immunoblotted for Thr-183/Thr-185-phospho-JNK (P-JNK), total JNK, and CHOP.
Fig. 2.
Fig. 2.
Cytoplasmic Ca2+ mobilization is necessary for enhanced TLR4-dependent JNK activation and apoptosis. (A) Macrophages were incubated for 0.25–2 h with the indicated reagents, alone or in combination: thapsigargin (Tg; 0.5 μM), fucoidan (Fuc; 50 μg/ml), A23187 (2 μg/ml), tunicamycin (Tn; 2 μg/ml), and LPS (500 pg/ml). Cell lysates were immunoblotted for Thr-183/Thr-185-phospho-JNK (P-JNK) and total JNK. (B) Macrophages were preincubated for 10 min with vehicle control or 15 μM BAPTA. The cells then were treated with 50 μg/ml acetyl-LDL (Ac-LDL) or acetyl-LDL plus 58035 (FC loading) for 12 h. Lysates were immunoblotted for Thr-183/Thr-185-phospho-JNK, and total JNK. (C) Macrophages were preincubated for 10 min with vehicle control or 5 μM BAPTA-AM. The cells then were incubated for 24 h with 50 μg/ml acetyl-LDL alone or in combination with 58035, 0.5 μM thapsigargin, or thapsigargin plus 50 μg/ml fucoidan. The cells were assayed for apoptosis.
Fig. 3.
Fig. 3.
Fucoidan-induced suppression of the IRF3-IFN-β branch of TLR4 signaling correlates with apoptosis in ER-stressed macrophages. (A) Macrophages were incubated for 24 h with thapsigargin (Tg), thapsigargin plus fucoidan (Fuc), or thapsigargin plus increasing concentrations of LPS. The cells then were assayed for apoptosis. (B) Macrophages were incubated for the indicated times with thapsigargin plus fucoidan or with thapsigargin plus 500 ng/ml LPS. Nuclear extracts were immunoblotted for IRF3, p65, α-tubulin, and nucleophosmin. (C) WT or Tlr4del macrophages were incubated for 6 h with thapsigargin plus fucoidan or with thapsigargin plus LPS. The media were collected and assayed by ELISA for IFN-β and RANTES.
Fig. 4.
Fig. 4.
SRA-dependent suppression of IFN-β contributes to macrophage apoptosis. (A) WT or Sra−/− macrophages were incubated for 6 h with thapsigargin plus fucoidan (Tg + Fuc) or thapsigargin plus 500 pg/ml LPS. The media then were assayed for IFN-β (∗, P < 0.001 vs. WT Tg + Fuc). (B) Macrophages were incubated for 18 h with thapsigargin alone, fucoidan alone, thapsigargin/fucoidan plus increasing concentrations of recombinant IFN-β, or IFN-β alone. The cells then were assayed for apoptosis as described in Fig. 1. (C) Macrophages were incubated for 24 h with thapsigargin, thapsigargin plus 1 ng/ml LPS, thapsigargin/LPS plus 50 units/ml anti-IFN-β neutralizing antibody, or thapsigargin/LPS plus an equivalent amount of rabbit IgG control antibody. The cells then were assayed for apoptosis. Representative fluorescent images and quantitative apoptosis data for each condition are shown. (D) Model of SRA-mediated alteration of TLR4 signaling from prosurvival to proapoptosis. See text for details.
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