Fine tuning inflammation at the front door: macrophage complement receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis.
Fine tuning inflammation at the front door: macrophage complement receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis.
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DOI：
10.1371/journal.ppat.1003114
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Schlesinger LS
中科院分区：
文献类型：
--
作者：
Dai S;Rajaram MV;Curry HM;Leander R;Schlesinger LS
补体受体3（CR 3，CD 11b/CD 18）是一种主要的巨噬细胞吞噬受体。CR 3调节免疫应答的生化途径尚未完全表征。土拉热弗朗西丝菌是一种引起土拉菌血症的巨噬细胞的显著感染性兼性细胞内病原体。早期逃避宿主免疫应答有助于F.土拉菌和CR 3是其吞噬作用的重要受体。在这里，我们证实了高毒力A型F的有效附着和摄取。土拉菌属人单核细胞衍生的巨噬细胞（hMDM）对土拉菌菌株Schu S4的作用需要补体C3调理作用和CR 3。然而，尽管C3调理作用后摄取增加>40倍，但与未调理的Schu S4和低毒性F. novicida。这表明CR 3通过调理的Schu S4的参与特别有助于吞噬期间和之后不久的免疫抑制，我们通过hMDM中的CD 11b siRNA敲低证实了这一点。这种免疫抑制伴随着ERK 1/2、p38 MAPK和NF-κB活化的早期抑制。此外，TLR 2 siRNA敲低显示响应于非调理的Schu S4的促炎细胞因子产生和MAPK活化依赖于TLR 2信号传导，提供了CR 3-TLR 2串扰介导调理的Schu S4的免疫抑制的证据。CD 11b胞质尾区的缺失逆转了调理剂处理的Schu-S4感染过程中CR 3介导的ERK和p38激活的降低。参与这种免疫抑制的CR 3介导的信号传导途径包括林恩激酶和Akt活化，以及增加的MKP-1，其限制了TLR 2介导的促炎反应。这些数据表明，虽然高毒力F。土拉热利用CR 3进行有效摄取，该受体的最佳接合通过由外向内信号传导抑制MAPK活化来下调TLR 2依赖性促炎反应。CR 3连锁免疫抑制是F.土拉菌感染高度致命的土拉热弗朗西丝菌可以在少于10个细菌的情况下引起人类呼吸道疾病。在体内，它主要在巨噬细胞内复制。逃避和/或抑制宿主的保护性免疫反应是弗朗西斯菌在哺乳动物中的毒力所必需的。然而，这种免疫抑制的详细分子机制尚不清楚。在这里，我们表明，这种病原体操纵的串扰两个重要的受体介导的途径在人类巨噬细胞：CR 3介导的吞噬作用和TLR 2介导的促炎反应。通过最佳地接合CR 3，弗朗西斯菌不仅获得有效的进入巨噬细胞，而且还抑制TLR 2介导的免疫应答，导致相对“沉默”的进入，使其能够在细胞内早期复制到高数量。土拉热在初次感染期间作为人类病原体。
Complement receptor 3 (CR3, CD11b/CD18) is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs) requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-κB activation. Furthermore, TLR2 siRNA knockdown shows that pro-inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro-inflammatory responses by inhibiting MAPK activation through outside-in signaling. CR3-linked immune suppression is an important mechanism involved in the pathogenesis of F. tularensis infection. The highly virulent Francisella tularensis can cause respiratory disease in humans with less than 10 bacteria. In vivo, it replicates mainly within macrophages. Evasion and/or suppression of the host protective immune response is essential to Francisella's virulence in mammals. However, the detailed molecular mechanisms for this immune suppression are not clear. Here we demonstrate that this pathogen manipulates the crosstalk between two important receptor-mediated pathways during entry in human macrophages: CR3-mediated phagocytosis and TLR2-mediated pro-inflammatory responses. By optimally engaging CR3, Francisella not only gains efficient access to macrophages but also dampens TLR2-mediated immune responses, leading to a relatively “silent” entry that allows it to replicate intracellularly to high numbers early on. Thus, we have identified an important mechanism that is critical for the success of F. tularensis as a human pathogen during primary infection.
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影响因子：
4.2
作者：
Barel, Monique;Hovanessian, Ara G.;Meibom, Karin;Briand, Jean-Paul;Dupuis, Marion;Charbit, Alain
通讯作者：
Charbit, Alain
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
3.1
作者：
Cole, Leah E.;Shirey, Kari Ann;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
5.5
作者：
Fraser, Deborah A.;Bohlson, Suzanne S.;Tenner, Andrea J.
通讯作者：
Tenner, Andrea J.