IL-33 receptor (ST2) deficiency downregulates myeloid precursors, inflammatory NK and dendritic cells in early phase of sepsis

Abstract

BackgroundSepsis is a life-threatening disease mediated by profound disturbances in systemic inflammatory response to infection. IL-33 is multifunctional regulator of numerous aspects of innate and adaptive immune response. The aim of this article was to further evaluate the role of IL-33 receptor (ST2) in different pathways of innate immunity during early polymicrobial sepsis.MethodsPolymicrobial sepsis was induced using cecal ligation and puncture (CLP) model in ST2 deficient (ST2−/−) and wild type BALB/c mice. Peritoneal and spleen cells were isolated for further phenotyping. Apoptosis was determined by immunohistochemistry and flow cytometry.ResultsDeletion of ST2 leads to increased susceptibility to early manifestations of sepsis as evaluated by clinical signs and survival. These are accompanied by decrease in the total number of neutrophils, eosinophils and mast cells in peritoneal cavity 12 h after CLP. In early sepsis there was also low number of precursors of myeloid cells in particular CD11b+Ly6G+Ly6Clow cells in spleen of ST2−/− mice. Although the number of NK cells in the spleen was similar, there were significant differences in the presence of inflammatory IFN-γ and IL-17 producing NK cells. Further, ST2 deletion affects the phenotype and maturation of dendritic cell in sepsis. The total number of dendritic cells in the spleen was lower as well as IL-12 expressing dendritic cells. Finally, there was higher frequency of active caspase-3 positive and early apoptotic cells, in particular CD11c positive cells, in spleen of septic ST2−/− mice.ConclusionTaken together, our data provide the evidence that ST2 deficiency in early phase of sepsis downregulates myeloid precursors, inflammatory NK and dendritic cells.

IL-17, IL-27, and IL-33: A Novel Axis Linked to Immunological Dysfunction During Sepsis

“…One group reported that the administration of IL-33 actually enhanced the production of IL-17 while decreasing the levels of IL-6, IL-10, and IFNγ following CLP (41). Similarly, another group found that the deletion of the IL-33 receptor ST2 led to a reduction in the frequency and number of IL-17 producing NK cells after CLP (86). However, a recent study of human patients with Staphylococcus aureus bacteremia revealed that a higher ratio of Th17 to Th1 cytokines early after sepsis onset was associated with increased mortality (49).…”

“…The ability of IL-33 to improve survival during sepsis is linked to the rescue of neutrophil migration to the site of infection (40), to improvements in bacterial clearance, and to a reduction in lymphocyte apoptosis (41). IL-33 also suppresses the inflammatory response by a variety of innate lymphocytes (86) and modulates the activity of ILC2 cells (47–49). In addition to direct effects on other lymphocytes, IL-33 impacts the activity of other cytokines, including IL-17 (41, 87).…”

Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage

“…The pathway has been implicated in multiple inflammatory disorders including asthma, 38 chronic obstructive pulmonary disease, 39 and inflammatory bowel disease 40 and vascular disease including acute myocardial infarction 41,42 and heart failure. 43 Studies into the mechanism of ST2-IL33 action initially focused on T lymphocytes, 44-46 but more recent data implicate the system in the regulation of innate immune components including NK cells 47-49 and macrophages. 50 The current study supplements these findings with further evidence for a role of sST2 in modifying the NK and monocyte response to IPH.…”

OGDH is involved in sepsis induced acute lung injury through the MAPK pathway

“…We used a CLP-induced mouse model of sepsis. Studies have shown that in addition to lung inflammatory damage, CLP-induced model animals also produce organ damage and the rise of pro-inflammatory cytokines in the myocardium, liver, spleen, kidney, and digestive tract (25)(26)(27)(28)(29)(30)(31). From the perspective of pathogenesis, the causes that induce sepsis and subsequent organ damage include inflammatory response disorder, immune dysfunction, mitochondrial damage, coagulation dysfunction, neuroendocrine-immune network abnormality, endoplasmic reticulum stress, and autophagy (32)(33)(34)(35)(36).…”