Interleukin-9 promotes intestinal barrier injury of sepsis: a translational research

Abstract

Background Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Intestinal mucosal barrier injury is one of the important manifestations of sepsis. Interleukin-9 (IL-9) and IL-9-producing CD4(+) T cells were emerging pro-inflammatory mediators with development of intestinal injury. However, it is unclear whether IL-9 is related to the intestinal barrier injury of sepsis. Methods To investigate the roles of IL-9-producing CD4(+) T cells and IL-9 in the process of barrier injury in sepsis, serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were measured in septic patients and controls. The markers of barrier function in serum and intestinal tissue were also collected in septic rats. Moreover, the barrier injury degree and survival rate of septic rats were also investigated after increasing or interfering with IL-9 expression. Results The serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were significantly higher in septic patients or rats than those in controls. IL-9-producing CD4(+) T cells and IL-9 levels were positively correlated with D-lactate levels and had a high predictive value of 28-day mortality in septic patients. The non-survivors had significantly higher serum T cell percentages, IL-9, and D-lactate levels compared with survivors. In septic rats, IL-9 increased the expression levels of D-lactate, whereas that decreased the expression levels of zonula occludens 1. Moreover, the barrier injury was aggravated or alleviated by increasing or interfering with IL-9 expression, respectively. Survival rate analysis also showed that IL-9 decreased the 14-day survival rate of septic rats. Conclusion IL-9 is closely related to intestinal mucosal barrier injury and mortality in sepsis. IL-9 blockade has the potential to improve the barrier injury in sepsis. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT03791866, Date: December 2018).

Integrin αEβ7 is involved in the intestinal barrier injury of sepsis

“…Furthermore, IL-9 and E-cadherin may exert a feedback relation via underlying pathways, although the exact mechanisms were not recognized. The differences in the proportions of Th9 cells or the levels of IL-9 were consistent with the findings of our previous study [ 15 ].…”

“…The underlying mechanisms of intestinal barrier injury in sepsis have not been clarified. Besides the regular T helper lymphocytes, Th9 cells was found to be involved in the acute intestinal damage of sepsis through the IL-9 pathway in our previous study [ 15 ]. However, it is not clear how the Th9 cells are regulated in sepsis.…”

“…Zhejiang Academy of Medical Sciences' animal facility (Zhejiang, China) provided adult SD rats aged between 6-8 weeks and weighing between 180-220g. As described in our previous study, sepsis was stimulated by means of the commonly used procedure of cecum ligation and puncture (CLP) [ 15 ]. The rats were anesthetized using 10 percent chloral hydrate (0.3 ml/100 g) injected intraperitoneally.…”

“…Adeno-associated virus (AAV) of αEβ7 interference was administered to the sepsis+αEβ7i cohort rats by intraperitoneal injection, whereas AAV of αEβ7 overexpression was administered to the sepsis+αEβ7e cohort rats. The production of AAV referred to our previous research [ 15 , 18 ]. Briefly, cDNA clone fragment encoding αEβ7 or αEβ7 shRNA cassette were transferred into rAAV plasmid, respectively (Genepharma, Shanghai, China).…”

“…A study by Nalleweg et al [ 14 ] showed that the expression of interleukin-9 receptor was substantially elevated in gut epithelial cells and that IL-9 was involved in the development of ulcerative colitis. Our recent research also determined that the proportions of Th9 cells, as well as the expression levels of IL-9, were particularly associated with acute intestinal barrier dysfunction in sepsis [ 15 ]. Therefore, IL-9 and Th9 cells may be possible targets for the treatment of gastrointestinal dysfunction in early sepsis.…”