Fractalkine and CX3CR1 Mediate Leukocyte Capture by Endothelium in Response to Shiga Toxin

Zanchi, Cristina; Zoja, Carla; Morigi, Marina; Valsecchi, Federica; Liu, Xue Yan; Rottoli, Daniela; Locatelli, Monica; Buelli, Simona; Pezzotta, Anna; Mapelli, Paola; Geelen, Joyce; Hawiger, Jacek

doi:10.4049/jimmunol.181.2.1460

Cited by 35 publications

(28 citation statements)

References 75 publications

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“…In a baboon model of HUS, LPS increased the toxicity of Stx (58). Consistently, both Stx2 and LPS were required to elicit a HUS-like response in mice (16,36,42). Our experiments document that in mice treated with Stx2/LPS that developed thrombocytopenia and renal failure, enhanced P-selectin expression on glomerular endothelial cells preceded C3 deposits.…”

Section: Discussionsupporting

confidence: 56%

“…The dosing protocol was based on previous studies (16,36). Mice were sacrificed at 3, 6, 24, or 48 h after injection.…”

Section: Experimental Model Of Husmentioning

confidence: 99%

“…After STEC ingestion, Stx is transported in the circulation to the capillary bed of target organs, including the kidney (5,6). Glomerular endothelium that expresses the receptor globotriaosyl ceramide (Gb3)/CD77 (10,11) is the main target of the toxic effects of Stx1 and 2 (12), which activate a cascade of signals contributing to vascular dysfunction, leukocyte recruitment, and thrombus formation (13)(14)(15)(16)(17)(18)(19). We previously reported that Stx promoted von Willebrand factor (VWF)-dependent thrombus growth on microvascular endothelium under flow via upregulation of P-selectin (17).…”

mentioning

confidence: 99%

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Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Morigi

Galbusera

Gastoldi

et al. 2011

The Journal of Immunology

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211

201

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Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti–P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.

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Section: Discussionsupporting

confidence: 56%

“…The dosing protocol was based on previous studies (16,36). Mice were sacrificed at 3, 6, 24, or 48 h after injection.…”

Section: Experimental Model Of Husmentioning

confidence: 99%

mentioning

confidence: 99%

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Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Morigi

Galbusera

Gastoldi

et al. 2011

The Journal of Immunology

Self Cite

211

201

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“…Kidney biopsies from D+HUS children showed mononuclear and PMNs within the glomeruli, along the zone of microvascular injury (41,42). In vitro, Stx promoted leukocyte adhesion and transmigration across glomerular endothelial cells via upregulation of adhesion molecules and chemokines (24,43). In TM LeD/LeD mice, the increased accumulation of leukocytes in the kidneys after Stx2/LPS injection was associated with overexpression of PECAM-1, a transmembrane glycoprotein belonging to the Ig superfamily of adhesion molecules with functional roles in leukocyte transendothelial cell migration (25,26).…”

Section: Discussionmentioning

confidence: 99%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TMwt/wt) and mice that lack the lectin-like domain of TM (TMLeD/LeD), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TMLeD/LeD mice exhibited more severe thrombocytopenia and renal dysfunction than TMwt/wt mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TMLeD/LeD than in TMwt/wt mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TMLeD/LeD mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TMLeD/LeD mice with HUS had a higher mortality rate than TMwt/wt mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.

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“…It is involved in atherosclerosis, 26,[41][42]45,46 vascular and renal inflammation 37,48,53 and cancer, 50 it stimulates actin reorganization in microglia 49,54 and it promotes leukocyte-renal endothelial cell interactions during hemolytic uremic syndrome, thereby contributing to the renal microvascular dysfunction and thrombotic microangiopathy. 55,56 To improve our understanding of the biological role of the interaction between fractalkine and CX 3 CR1 in monocytic populations, we analyzed CX 3 CR1 surface protein expression as well as mRNA expression in freshly Mo, MAC and DC populations.…”

Section: Cr1 Gene Expression In Mos Macs and Dcsmentioning

confidence: 99%

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

et al. 2014

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Circulating monocytes (Mos) may continuously repopulate macrophage (MAC) or dendritic cell (DC) populations to maintain homeostasis. MACs and DCs are specialized cells that play different and complementary immunological functions. Accordingly, they present distinct migratory properties. Specifically, whereas MACs largely remain in tissues, DCs are capable of migrating from peripheral tissues to lymphoid organs. The aim of this work was to analyze the expression of the fractalkine receptor (CX 3 CR1) during the monocytic differentiation process. Freshly isolated Mos express high levels of both CX 3 CR1 mRNA and protein. During the Mo differentiation process, CX 3 CR1 is downregulated in both DCs and MACs. However, MACs showed significantly higher CX 3 CR1 expression levels than did DC. We also observed an antagonistic CX 3 CR1 regulation by interferon (IFN)-c and interleukin (IL)-4 during MAC activation through the classical and alternative MAC pathways, respectively. IFN-c inhibited the loss of CX 3 CR1, but IL-4 induced it. Additionally, we demonstrated an association between CX 3 CR1 expression and apoptosis prevention by soluble fractalkine (sCX 3 CL1) in Mos, DCs and MACs. This is the first report demonstrating sequential and differential CX 3 CR1 modulation during Mo differentiation. Most importantly, we demonstrated a functional link between CX 3 CR1 expression and cell survival in the presence of sCX 3 CL1.

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Fractalkine and CX3CR1 Mediate Leukocyte Capture by Endothelium in Response to Shiga Toxin

Cited by 35 publications

References 75 publications

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation

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