IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice.

IL-33 is a newly discovered member of the IL-1 family and has been identified as a potent inducer of Th2 type immunity. Emerging evidence imply that IL-33 may also act as an alarm to alert the immune system when released by epithelial barrier tissues during trauma or infection. In this study, we further investigate the potential efficacy of IL-33 on dermal wound healing in streptozotocin-induced diabetic mice. A full-thickness skin wound was generated on the back of diabetic mice and treated with IL-33 or vehicle topically. Our data showed that IL-33 delivery contributed to diabetic wound closure with wounds gaping narrower and exhibiting elevated re-epithelialization. IL-33 promoted the new extracellular matrix (ECM) deposition and angiogenesis formation, which indicates an important role of IL-33 on matrix synthesis and neovascularization. Meanwhile, IL-33 accelerated the development of M2 macrophages in wound sites in vivo, and amplified IL-13-induced polarization of bone marrow-derived macrophages toward a M2 phenotype in vitro. Furthermore, IL-33-amplified M2 macrophages augmented the proliferation of fibroblasts and ECM deposition. All together, these results strongly suggest manipulation of IL-33-mediated signal might be a potential therapeutic approach for diabetic skin wounds.

Astragaloside IV alleviates E. coli-caused peritonitis via upregulation of neutrophil influx to the site of infection.

Astragaloside IV (AS-IV), an active saponin purified from Astragali Radix, has been identified with broad biological and pharmacological activities. In the present study, we continue to explore the potential effect of AS-IV on antibacterial response using an acute E. coli peritoneal infection model. Our findings implied that administration of AS-IV decreases mortality in mice challenged by lethal E. coli infection. The protection of AS-IV was related to promotion of neutrophil extravasation into the peritoneum and bacterial clearance. Toll-like receptor (TLR) activation in neutrophils has been reported to reduce CXCR2 expression and subsequent neutrophil migration. Our data indicated that AS-IV prevented the reduction of CXCR2 expression and neutrophil migration induced by LPS, the activator for TLR4. Moreover, we found that AS-IV blocks LPS-induced suppression of CXCR2 on neutrophils by inhibiting the expression of G protein-coupled receptor kinase-2 (GRK2), an agonist that regulates desensitization and internalization of chemokine receptors. Taken together, these data propose that AS-IV, through modulating GRK2-CXCR2 signal in neutrophils, offers an essential efficacy on host antibacterial immunity.

Astragaloside IV enhances diabetic wound healing involving upregulation of alternatively activated macrophages.

Astragaloside IV (AS-IV), one of the major active compounds extracted from Astragali Radix, has been used experimentally for its potent antiinflammatory and immunoregulatory activities. In this study, we further investigate the potential efficacy of AS-IV on impaired wound healing in streptozotocin-induced diabetic mice. A full-thickness skin wound was produced on the back of diabetic mice and treated with AS-IV or vehicle topically. Our results showed that AS-IV application promoted diabetic wound repair with wounds gaping narrower and exhibiting augmented reepithelialization. AS-IV enhanced the collagen deposition and the expression of extracellular matrix (ECM)-related genes such as fibronectin and collagen IIIa, which implies a direct effect of AS-IV on matrix synthesis. AS-IV also improved the new blood vessel formation in wound tissue with increased numbers of endothelial cells and enhanced expression of VEGF and vWF. Moreover, the beneficial effect of AS-IV was related to the development of polarized alternatively activated macrophages, which involved in resolution of inflammation and facilitation of wound repair. All together, these findings suggest that AS-IV may play a potential effect on maintenance of cutaneous homeostasis and acceleration of diabetic wound healing.

Interleukin-33 facilitates neutrophil recruitment and bacterial clearance in S. aureus-caused peritonitis.

Interleukin (IL)-33, a newly recognized member of IL-1 family of cytokines, plays an important role in polarizing Th2-associated immunity. Recently growing evidence indicates that IL-33 also represents a crucial mediator of antimicrobial infection. In this study, we investigated the effect of IL-33 on antibacterial response using an acute Staphylococcus aureus peritoneal infection model. Our results showed that IL-33 administration induced a rapid bacterial clearance and markedly reduced the S. aureus infection-related mortality. IL-33-treated mice displayed increased neutrophil influx into the focus of infection and higher concentrations of chemokine CXCL2 in the peritoneum than untreated mice. The beneficial effect of IL-33 priming was related to reversal of the S. aureus-induced reduction of CXCR2 expression on the surface of neutrophils. Furthermore, conditioning of neutrophils by IL-33 led to the enhancement of complement receptor 3 expression induced by S. aureus, which in turn facilitates the phagocytosis of opsonized S. aureus. Finally, neutrophils primed by IL-33 upregulated the production of reactive oxygen species and the subsequent killing activity for S. aureus. All together, these findings suggest that IL-33, through regulating multiple steps of neutrophil-mediated bactericidal function, provides a profound effect in host antimicrobial defense response.

Sphingosine-1-phosphate receptor 1 agonist SEW2871 prolongs heterotopic heart allograft survival in mice.

Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune cell trafficking. Recent studies have revealed immunomodulatory functions of S1P and its receptors (S1PR1-S1PR5) in many inflammatory conditions, such as asthma and autoimmunity. Here, we explore the efficacy of SEW2871, a selective S1PR1 agonist, in the prevention of acute allograft rejection in a murine cardiac transplantation model. Treatment of recipient mice with SEW2871 significantly prolongs cardiac allograft survival as compared to those recipients treated with control vehicle. The enhanced graft survival is associated with reduced circulating lymphocytes and allograft inflammatory cell infiltration. The cytokine analysis showed decreased allograft expression of TNF-α, IFN-γ and IL-2 in the SEW2871-treated mice. Moreover, administration of SEW2871 increases the percentage of CD4(+) T regulatory cells and FoxP3 expression in spleen of allograft recipients. Therefore, SEW2871 plays a critical role in regulation of lymphocyte trafficking and development, which directly contributes to prolongation of the allograft survival.

[Amelioration of inflammatory reaction in patients with severe sepsis with inosine].

OBJECTIVE: To evaluate the therapeutic effect of inosine in patients with severe sepsis. METHODS: A prospective study was conducted. Eighty-five severe sepsis patients hospitalized in intensive care unit (ICU) from March 2011 to August 2012 were included and randomized into three groups: 25 cases as conventional therapy group, who were treated with routine treatments; 28 patients were given inosine within 6 hours besides routine treatments; 32 patients were given inosine after 6 hours together with routine treatments. Inosine was given in the latter two groups by intravenous infusion (600 mg twice a day) for 10-14 days or to the end of the research when patients died or discharged from ICU. Before or after the treatment, venous blood was collected for determination of pro-inflammatory factors and organ function parameters. Average duration of stay in ICU and mortality rate were analyzed. RESULTS: Compared with conventional therapy group, the levels of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) were decreased in inosine in both within 6-hour and after 6-hour groups (TNF-α: 9.6 ± 4.1 ng/L, 10.8 ± 2.8 ng/L vs. 18.2 ± 3.3 ng/L, IL-6: 123.0 ± 10.1 ng/L, 132.0 ± 18.4 ng/L vs. 172.0 ± 17.9 ng/L, CRP: 42.0 ± 10.3 mg/L, 45.0 ± 8.6 mg/L vs. 61.0 ± 12.7 mg/L, all P<0.05), but there was no statistical significance in the content of IL-10 (53.0 ± 9.4 ng/L, 56.0 ± 10.8 ng/L vs. 58.0 ± 11.2 ng/L, both P>0.05). The lowering of alanine transaminase (ALT), total bilirubin, B-type natriuretic peptide (BNP), oxygenation index was more marked in inosine within 6-hour and after 6-hour groups than those of conventional therapy group (ALT: 42.0 ± 10.8 U/L, 46.0 ± 7.9 U/L vs. 63.0 ± 9.4 U/L, total bilirubin: 16.3 ± 6.7 µmol/L, 18.3 ± 7.3 µmol/L vs. 28.1 ± 8.5 µmol/L, BNP: 322.0 ± 28.7 ng/L, 347.0 ± 31.4 ng/L vs. 428.0 ± 43.2 ng/L, oxygenation index: 210.0 ± 23.8 mm Hg, 198.0 ± 21.4 mm Hg vs. 163.0 ± 15.2 mm Hg, all P<0.05). However, the difference of these values showed no significant difference between the two inosine groups (all P>0.05). There was no statistical significance in ICU stay days (22.4 ± 6.3 days, 19.8 ± 4.6 days, 23.1 ± 5.2 days) and mortality rate (36.0%, 32.1%, 34.4%) among three groups (all P>0.05). CONCLUSION: For severe sepsis patients, on the base of routine treatments, normal dose of inosine can lower the level of pro-inflammatory factors and ameliorate organ function, but it cannot decrease average ICU stay days and mortality rate.