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DC-SIGN Expression in Intestinal Epithelial Cells Regulates Sepsis-Associated Acute Intestinal Injury Via Activating ERK1/2-NF-κB/P65 Signaling

Chen, Weiwei; Ma, Li; Li, Ranran; Huang, Shunwei; Xie, Rongli; Chen, Ying; Zhao, Bing; Fei, Jian; Qu, Hongping; Chen, Hao; Mao, Enqiang; Chen, Er-zhen

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doi: 10.1097/SHK.0000000000001277
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Gastrointestinal (GI) dysfunction is frequently encountered in critical illness. Approximately 60% of patients exhibit at least one GI problem during their intensive care unit (ICU) stay (1). There is also increasing evidence that GI dysfunction is associated with poor outcomes concerning mortality (2, 3).

The GI tract has various functions, including digestion, absorption, endocrine, immune, and barrier, which lead to the complicated and even undefined mechanisms of the pathogenesis of GI dysfunction (4). Sepsis is a life-threatening syndrome of dysregulated inflammatory response caused by severe infection (5). To date, GI dysfunction during sepsis remains poorly investigated although numerous important hypotheses, such as that sepsis results in initial hit to gut and the gut can act as the “motor” of critical illness, have been proposed (6, 7). Therefore, the exact relationship between gut and sepsis still needs to be elucidated.

Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is a C-type lectin that is generally expressed on dendritic cells (DCs) (8). As an antigen-capturing receptor, DC-SIGN could rapidly recognize and internalize antigens, thereby presenting them to CD4+ T cells to trigger the subsequent immune response (8, 9). Our previous work demonstrated that hypoxia and hemorrhagic hypotension significantly induced DC-SIGN expression in rat intestine epithelial cells (IECs) both in vitro and in vivo, and its expression aggravated intestinal injury as well as the secretion of systemic proinflammatory cytokines (10). In addition, several studies have discovered that DC-SIGN was also overexpressed on GI epithelial cells in chronic inflammatory diseases, such as inflammatory bowel diseases (IBD), Helicobacter pylori (H. pylori)-induced gastritis, and gastric ulcer. In this instance, DC-SIGN upregulation in the GI epithelial cells is associated with cells that have a high antigen-presentation potential and consequently mediate T-helper cell differentiation which may be involved in GI mucosal inflammatory injury (11, 12). However, the role of DC-SIGN expressed by IECs in sepsis-induced acute intestinal injury is still unknown.

In the present study, we aimed to investigate the expression of DC-SIGN in the intestinal tissues of mice with sepsis induced by cecal ligation and puncture (CLP) as well as its significance in multiple organ injuries and systemic inflammatory response. Furthermore, we studied the potential mechanisms of DC-SIGN in regulating acute intestinal injury during the early phase of sepsis.



Male C57BL/6 mice (aged 6–10 weeks, 22–28 g) were purchased from Slac Laboratory Animal Corporation, Shanghai, China. All mice were acclimated and maintained in a temperature-controlled (25 ± 0.5°C) and air-conditioned (humidity 50%–60%) environment with a 12/12-h light/dark cycle, and were provided with free access to water and food (LabDiet, St. Louis, Mo). All animal studies were approved by the Animal Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, adhered to the international guidelines for care and use of laboratory animals.

CLP model

Sham and CLP operation were performed under ketamine hydrochloride (75 mg/kg) and xylazine (15 mg/kg) anesthesia as previously described (13). Mice were resuscitated with a 50 mL/kg subcutaneous injection of sterile saline at the end of surgery and had unlimited access to food and water. Mice were euthanized by decapitation at 6, 12, and 24 h postsurgery. Tissues and serum were isolated, flash frozen, and stored at −80°C.

DC-SIGN siRNA transfection in vivo

Mouse DC-SIGN or Negative Control (NC) siRNA (dissolved in RNAse-free sterile saline to 1 mg/mL; GenePharma, Shanghai, China) were administered to mice by intraperitoneal injection at 48 h before CLP. siRNA at the dose of 10 mg/kg was selected to be effective and safe for mice based on our results of preexperiments (data not shown). Mice injected with sterile saline were taken as control. The sequences of mouse DC-SIGN siRNA were chemically modified by 2′-Ome and were listed as followed: DC-SIGN siRNA1: 5′-GGUGC UCUUC CUAGC UGUUTT-3′ (sense), 5′-AACAG CUAGG AAGAG CACCTT-3′ (antisense); DC-SIGN siRNA2: 5′-GGCCC AGAAG UCCUG GAAUTT-3′ (sense), 5′-AUUCC AGGAC UUCUG GGCCTT-3’(antisense); DC-SIGN siRNA3: 5′-GCCAC ACCAG GCACU CCAUTT-3′ (sense), 5′-AUGGA GUGCC UGGUG UGGCTT-3′ (antisense). The transfection efficiency was detected by western blot and flow cytometry analysis.

Mouse IECs isolation and flow cytometry

Isolation of IECs from mouse intestinal tissues was as previously described (14). Briefly, intestines were cut into 4 to 5 cm pieces and placed in ice-cold PBS. Feces and residual mesenteric fat tissue were carefully removed. The intestine pieces were opened longitudinally, cut into 1 cm pieces, and washed with ice-cold PBS. The cut pieces were incubated in HBSS (Solarbio, Beijing, China) containing 5 mM EDTA (Sigma) and 1 mM DTT (Sigma) for 20 min at 37°C with slow rotation (40 g). The solution was allowed to go through a 70 μm cell strainer (Falcon352350; Corning, Durham, NC) to collect IECs.

Mouse IECs were sorted by flow cytometry using anti-mouse APC-CD326 (epithelial cell adhesion molecule, 563478; BD Bioscience, San Diego, Calif) and were incubated with Fixable Viability Dye eFluor 780 (FVD; eBioscience, San Diego, CA) to distinguish the live cells from the dead cells. To evaluate DC-SIGN expression, IECs were stained with CD209a conjugated with BV605 (BV605-CD209a, 747825; BD Bioscience, San Diego, CA). Stained samples were fixed with 2% paraformaldehyde and analyzed on an LSRFortessa flow cytometer (BD Biosciences, San Diego, CA).


FHs74Int, a normal human small intestine epithelial cell line, was kindly provided by Stem Cell Bank, Chinese Academy of Sciences (Shanghai, China). This cell line exhibits the characteristics of primary cell. FHs74Int was cultured in Hybri-Care Medium (ATCC 46-X, Manassas, Va) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY), suspended with rhEGF (Sigma, SRP-3027) 30 ng/mL, and 1% penicillin-streptomycin (Millipore, TMS-AB2-C) at 37°C in a humidified atmosphere with 5% CO2.

To induce sepsis-associated IECs activation, FHs74Int was incubated with different doses of LPS (Sigma, St. Louis, Mo) (50, 100, 150, 200, and 250 ng/mL) for different time-points (6, 12, 24, and 48 h).

The ERK1/2-specific inhibitor SCH772984 (Selleck chemicals, Houston, Tex) was dissolved in DMSO for in vitro studies. The inhibition efficiency was detected by western blot analysis.

The supernatants and protein of FHs74Int cells were collected and stored at −80°C.

DC-SIGN siRNA transfection in vitro

Before transfection, FHs74Int cells were cultured in 6-well plates to the cell density of 60% to 70%. Then, FHs74Int cells were transfected with human DC-SIGN or NC siRNA (200 nM; GenePharma, Shanghai, China) with the transfection reagent lipofectamine 2000 (Invitrogen, Carlsbad, Calif) for 24 h. Transfected cells were then stimulated with 200 ng/mL LPS for 24 h. The sequences of human DC-SIGN siRNA were listed as below: DC-SIGN siRNA1: 5′-GGAAU GGACA UUCUU CCAATT-3′ (sense), 5′-UUGGA AGAAU GUCCA UUCCTT-3’ (antisense); DC-SIGN siRNA2: 5′-GGAUG AAGAA CAGUU UCUUTT-3′ (sense), 5′-AAGAA ACUGU UCUUC AUCCTT-3′ (antisense). The transfection efficiency was detected by western blot analysis.

Western blot

Protein samples (20 μg per sample) were subjected to 10% sodium dodecyl sulfate–polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes (Millipore, Temecula, Calif). After blocking with 5% non-fat dried milk at room temperature for 1 h, membranes were incubated with appropriate primary antibodies against DC-SIGN (Abcam, Cambridge, Mass), GAPDH, phosphorylated, and total nuclear factor-κB (NF-κB)/p65, as well as phosphorylated and total extracellular signal regulated kinase (ERK1/2) (Cell Signaling Technology, Danvers, Mass) overnight at 4°C. After proper washing, membranes were incubated for 1 h with HRP-conjugated secondary antibodies. The blots were detected with Western HRP Substrate (WBLUF0100; Millipore, Billerica, Mass). The results were visualized with Tanon 5500 Imaging System (Shanghai, China).


For immunohistochemical detection of DC-SIGN expression, fixed intestinal tissues were dehydrated in ascending grades of alcohol, embedded in paraffin, and sectioned at 7 μm. Sections were treated with endogenous peroxidase and nonspecific protein blocking, and were incubated with DC-SIGN primary antibody (1:100, sc-74589, Santa Cruz, Calif) at 4°C overnight. Phosphatebuffered saline was used for negative control. Then, sections were incubated with biotinylated secondary antibody (1:400; Invitrogen, Waltham, Mass) for 1 h at room temperature. Finally, the sections were stained by diaminobenzidine for microscopic examination (Olympus BX50, Japan).

Histological examination

The small intestine, lung, liver, and kidney tissues were fixed overnight in 4% paraformaldehyde, and stained for hematoxylin and eosin (H&E). The severity of organ injury was observed in the tissue sections and scored according to the scoring criteria as described previously (15–17). The severity of small intestine and kidney injury was scored on a scale from 0 to 4. The severity of lung and liver injury was scored on a scale from 0 to 3. All of the evaluations were performed on six fields per section under 100 × magnifications by two pathologists in a double-blind fashion.


The concentrations of TNF-α, IL-1β, IL-6, IL-10, and IFN-γ in mouse serum and culture supernatant of FHs74Int were assessed by enzyme-linked immunosorbent assay (ELISA) kits (MCYTOMAG-70K; Merck Millipore, Darmstadt, Germany), and all procedures were complied with the manufacturer's protocols.

Statistical Analysis

All statistics were performed using GraphPad Prism 5.0 (GraphPad Software, San Diego, Calif) and SAS 9.0 (SAS Institute, Cary, NC). All data were expressed as the mean ± standard deviations (SD). Differences between groups were analyzed using a one-way ANOVA and Mann–Whitney test. Survival curves were compared with a Kaplan–Meier test. All differences were considered statistically significant at P value of <0.05.


DC-SIGN expression in mouse and human IECs was significantly induced in sepsis

The protein expression of DC-SIGN was detected in the intestinal tissues of mice with sepsis induced by CLP. The results showed that while DC-SIGN was almost undetectable in the intestinal tissues of sham mice, its expression was significantly increased after 6, 12, and 24 h of CLP in a time-dependent manner (P < 0.05) (Fig. 1A). Moreover, the immunohistochemical staining results showed that DC-SIGN expression was mainly observed in mouse IECs (Fig. 1B).

Fig. 1
Fig. 1:
CLP and LPS stimulation induced the upregulation of DC-SIGN in IECs both in vivo and in vitro.

Based on our findings in septic mice, we next investigated the effect of LPS stimulation on DC-SIGN expression in human IECs. FHs74Int was stimulated with LPS at different doses for different time periods. As shown in Figure 1, C and D, DC-SIGN expression was significantly increased by LPS stimulation in a dose- and time-dependent manner, showing the highest upregulation by 200 ng/mL LPS at 24 h.

Our data indicated that sepsis stimuli could induce the expression of DC-SIGN in IECs both in vivo and in vitro.

The administration of DC-SIGN siRNA diminished CLP-induced upregulation of DC-SIGN in vivo

To obtain an optimal condition for DC-SIGN inhibition in vivo, mice were administered with DC-SIGN siRNA1, DC-SIGN siRNA2, DC-SIGN siRNA3, or NC siRNA via intraperitoneal injection 48 h before CLP. As shown in Figure 2A, the expression of DC-SIGN protein induced by CLP was markedly decreased when septic mice were pretreated with DC-SIGN siRNA1 (P < 0.0001), whereas the inhibitory effects of DC-SIGN siRNA2 or DC-SIGN siRNA3 on CLP-induced DC-SIGN expression were not statistically significant (P = 0.12 and 0.41, respectively). To further validate the knockdown effect of DC-SIGN siRNA1, IECs of these three groups of mice small intestinal tissues, including sham, CLP with NC siRNA pretreatment, and CLP with DC-SIGN siRNA1 pretreatment, were isolated and analyzed for DC-SIGN expression using flow cytometry. The results showed that at 24 h after surgery, the percentage of DC-SIGN+ IECs was significantly increased in the CLP mice injected with NC siRNA compared with the percentage in the sham group (45.33% vs. 7.46%, P < 0.0001). When mice were pretreated with DC-SIGN siRNA1, CLP-induced increase of DC-SIGN+ IECs was reduced to 29.6% (P = 0.029, Fig. 2, B and C). This result suggested that DC-SIGN siRNA1 could effectively inhibit CLP-induced DC-SIGN upregulation in mouse IECs.

Fig. 2
Fig. 2:
Inhibition efficiency of DC-SIGN siRNAs in intestinal tissues and IECs.

Inhibition of DC-SIGN expression in IECs reduced multiple organ injury, systemic inflammatory response, and improved survival rate of septic mice

H&E staining results showed that in sham mice, the histological structures of small intestine, lung, liver, and kidney were typical of a normal architecture (Fig. 3, A–D). After the induction of CLP at 24 h, we observed loss of epithelial and mucosal architecture, destruction of the villi, as well as inflammatory cells infiltration in the small intestine (Fig. 3E). The lung tissue has pulmonary edema and interstitial cell infiltration (Fig. 3F). Hepatic cell necrosis, loss of intercellular borders, and hemorrhage were observed in the liver (Fig. 3G). In addition, tubular cell swelling, tubular dilatation, and hemorrhage were shown in the kidney (Fig. 3H). Compared with the NC siRNA group, DC-SIGN siRNA1 pretreatment abolished the histopathologic damage in the small intestine, lung, liver, and kidney (Fig. 3, I–L). The injury scores of small intestine, lung, liver, and kidney were significantly decreased in the DC-SIGN siRNA1 pretreated CLP mice compared with the NC siRNA group (P < 0.05; Fig. 3, M–P).

Fig. 3
Fig. 3:
DC-SIGN siRNA pretreatment reduced organ damage and systemic cytokines levels after CLP.

Moreover, the serum levels of inflammatory cytokines TNF-α, IL-1β, IL-6, IL-10, and INF-γ were greatly increased after CLP challenge. Compared with the NC siRNA group, DC-SIGN siRNA1 pretreatment significantly decreased the levels of TNF-α (344.0 ± 46.66 pg/mL vs. 18.30 ± 4.01 pg/mL, P < 0.0001), IL-1β (629.20 ± 164.90 pg/mL vs. 26.07 ± 7.55 pg/mL, P = 0.0001), IL-6 (54,100 ± 1,891 pg/mL vs. 235.0 ± 52.05 pg/mL, P = 0.0003) at 24 h after CLP. Serum levels of IL-10 and INF-γ were also significantly decreased by DC-SIGN siRNA1 at both 6 and 24 h after CLP (Fig. 3Q).

In addition, the survival rate at 24 h after CLP was higher in DC-SIGN siRNA1 pretreated mice compared with NC siRNA pretreated mice (78.85% [15/19] vs. 57.90% [11/19], P = 0.077). At day 7 after CLP, the survival rate of mice pretreated with DC-SIGN siRNA1 was significantly higher than the mice pretreated with NC siRNA (52.63% vs. 26.32%, P = 0.020) (Fig. 4).

Fig. 4
Fig. 4:
Survival rate of CLP-induced septic mice was elevated by DC-SIGN siRNA pretreatment.

LPS-induced DC-SIGN expression in FHs74Int regulates the inflammatory response via mediating ERK1/2-NF-κB/p65

To investigate the underlying mechanisms of DC-SIGN in sepsis-induced organ injury and systemic inflammatory response, we analyzed the activation status of ERK1/2 and NF-κB/p65 in intestinal tissues of septic mice. We found that DC-SIGN expression by DC-SIGN siRNA1 pretreatment at 24 h after CLP was decreased, consistent with the effects of the inhibition of ERK1/2 and NF-κB/p65 signaling (Fig. 5, A–C).

Fig. 5
Fig. 5:
Inhibition of DC-SIGN blocked ERK1/2-NF-κB signaling activation.

To identify the effects of DC-SIGN inhibition on sepsis-related NF-κB and ERK1/2 activation in IECs, FHs74Int cells were transfected with DC-SIGN siRNAs or NC siRNA before stimulated with LPS. The results showed that the knockdown of DC-SIGN inhibited NF-κB/p65 and ERK1/2 phosphorylation significantly (P < 0.05; Fig. 6A). To further identify the relationship between NF-κB and ERK, FHs74Int cells were treated with ERK1/2 inhibitor SCH772984 (1 μM) before LPS (200 ng/mL) stimulation. We found that SCH772984, by inhibiting ERK1/2 phosphorylation, dramatically diminished LPS-induced phosphorylation of NF-κB/p65 (Fig. 6B). In addition, SCH772984 treatment had no effect on the expression of DC-SIGN in FHs74Int cells.

Fig. 6
Fig. 6:
DC-SIGN knockdown inhibited LPS-induced activation of ERK1/2-NF-κB signaling in FHs74Int cells.

Moreover, in FHs74Int cells, the knockdown of DC-SIGN and ERK1/2 inhibition both significantly inhibited the upregulation of TNF-α, IL-1β, IL-6, IL-10, and INF-γ induced by LPS (P < 0.05) (Fig. 6C). These findings indicated that LPS stimuli-induced DC-SIGN activated NF-κB signaling via the phosphorylation of ERK1/2 in IECs, thereby regulating LPS-induced inflammatory responses.


Sepsis-associated GI dysfunction may trigger the pathogenesis of multiple organ failure (4, 6, 7). The underlying mechanisms that regulate sepsis-induced acute intestinal injury are not known yet. Our present study found that the expression of DC-SIGN in IECs was induced both by CLP-induced sepsis in vivo and by LPS stimulation in vitro. In addition, we demonstrated that DC-SIGN led to the upregulation of inflammatory cytokines via activating ERK1/2-NF-κB/p65 signaling pathway in human IECs in vitro. Furthermore, the inhibition of DC-SIGN significantly diminished CLP-induced systemic inflammatory response and multiple organ injuries, resulting in improved survival rate of septic mice.

The GI tract is the most easily sacrificial organ at the early phase of sepsis (1, 3). Apart from digestion, it produces hormones, serves as a barrier, and plays a major role in immunological function (4). The abovementioned functions are mainly based on epithelial cells integrity and stability. In the matter of immune defense, IECs interact with intraepithelial immune cells to drive tolerogenic responses under homeostasis. Meanwhile, they can release several immune mediators, such as antimicrobial peptides (AMPs), C-type lectins, and cytokines, to recruit inflammatory cells and to elicit immunity to infectious agents (18). DC-SIGN, a kind of C-type calcium-dependent lectins, is a functional hallmark of DCs. It can capture antigens for processing and presentation, and mediating intercellular adhesion and migration as well as signaling (8, 9).

In fact, the phenomenon of epithelial cells expressing DC-SIGN has been reported to be involved in course of various GI inflammatory diseases. In our previous work, we found that hypoxia and hemorrhagic shock induced DC-SIGN expression in rat IECs, which is in parallel with the increase of local and systemic proinflammatory cytokines TNF-α and IL-6 secretion, as well as the aggravation of histological damage in intestine tissue (10). Similar phenomena have been observed by others in the occurrence and development of chronic infection or sterile inflammatory diseases. It has been reported that DC-SIGN was upregulated in the gastric epithelial cells infected with H. pylori and mediated T-helper-1 differentiation, which may be involved in H. pylori-induced gastric mucosal injury (11). It has been shown that DC-SIGN expression was significantly increased in IECs of patients with IBD and IECs derived from dextran sodium sulfate (DSS)-induced murine colitis model. Moreover, DC-SIGN expression was strongly correlated with the severity of IBD (12). The present study demonstrated that IECs highly expressed DC-SIGN during the early phase of sepsis. Suppression of DC-SIGN expression could diminish the overproduction of cytokines and alleviate multiple organ injury, leading to reduced mortality of septic mice.

A number of researches showed that DC-SIGN regulates immune responses through different signaling pathways. In monocyte-derived DCs, DC-SIGN induces ERK1/2 and Akt phosphorylation, and also triggers PLC-γ phosphorylation and transient increase of intracellular calcium (19). Moreover, DC-SIGN coprecipitates with the tyrosine kinases Lyn and Syk, crosslinking synergizes with TNF-α for IL-10 release (19, 20). These DC-SIGN triggered intracellular signals modulate DC maturation and preferentially evoke Th2-type immune responses (19, 21). NF-κB is a transcription factor that is a primary regulator of inflammatory cytokines in inflammation (22–24). There is increasing evidence that DC-SIGN mediates NF-κB to initiates inflammatory responses. However, the underlying signaling pathways remain a topic of debate. As a pattern recognition receptor, DC-SIGN recognizes and binds with numerous pathogens including HIV-1 gp120 to induce Raf-1-directed phosphorylation of the NF-κB/p65 and MEK/ERK pathway (23). It has been found that DC-SIGN participates in LPS-induced acute injury of human renal tubular epithelial cells (HK-2) via the Toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)-independent manner. LPS promotes DC-SIGN interactions with TLR-4, initiates IKB kinase (IKKε) and TANK-binding kinase 1 (TBK1) phosphorylation and activates NF-κB/p65 (24). Our in vivo data showed that CLP increased the phosphorylation levels of ERK1/2, IKKε, p38, and JNK (data not shown), whereas the knockdown of DC-SIGN specifically inhibited the upregulation of phospho-ERK1/2, which was confirmed by our in vitro findings. We furthermore showed that DC-SIGN knockdown inhibited CLP-induced activation of NF-κB/p65, which, in turn, decreased the levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6. Consistently, the knockdown of DC-SIGN in FHs74Int in vitro abolished LPS-induced NF-κB/p65 activation and cytokine secretion.

Excessive inflammation is a key event in sepsis, whose severity correlates with the degree of local and systemic injury (5, 25). This study demonstrated that DC-SIGN inhibition effectively suppressed the activation of ERK1/2 and NF-κB/p65 both in vitro and in vivo. Consistent with other studies, our results revealed that anti-DC-SIGN treatment can alleviate intestinal injury and systemic inflammatory responses by inhibiting the ERK and NF-κB pathways.

To our knowledge, this study is the first to illustrate the expression of DC-SIGN in IECs in murine model of sepsis. The primary limitation of our study is that the lack of acknowledged DC-SIGN knockout mouse models makes it difficult to address the function of DC-SIGN in vivo(9, 20, 26–28). Therefore, we chose siRNA transfection in vivo by intraperitoneal injection to knock down DC-SIGN, and the efficiency of knockdown was confirmed by our above results. In addition, we found that, besides the intestine, DC-SIGN expression in the lung, liver, and kidney tissues was also induced by CLP. The intraperitoneal injection of DC-SIGN siRNA primarily showed its effect on intestine, although had marginal effect on the lung, liver, and kidney. The inhibition of DC-SIGN in the intestine resulted in the improvement of survival. However, whether the systemic inhibition of DC-SIGN expression will improve the outcomes by other mechanisms still needs to be further studied.


In conclusion, our study demonstrated that anti-DC-SIGN intervention exhibited protective effects on IECs activated by sepsis. By suppressing the activation of ERK1/2 and NF-κB signaling, DC-SIGN inhibition effectively reduced the intestinal and systemic inflammatory responses as well as the mortality of septic mice. These results provided a new insight for better understanding of the mechanisms of sepsis-induced SIRS and MODS, and also indicated that DC-SIGN is potential to be a novel target for therapeutic intervention of sepsis-induced acute intestinal injury in the future.


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Acute intestinal injury; DC-SIGN; ERK1/2; intestinal epithelial cells; NF-κB; sepsis

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