Hyper-coagulation, hypothermia, systemic inflammatory responses and shock are major clinical manifestations of endotoxin shock syndrome in human. As previously reported, mice primed with heat-killed Propionibacterium acnes are highly susceptible to the action of LPS to induce tumour necrosis factor (TNF)-alpha and to that of TNF-alpha to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF-alpha and the development of individual symptoms after subsequent challenge with LPS or TNF-alpha. Propionibacterium acnes-primed wild-type (WT) mice, but not naive mice, exhibited hyper-coagulation with elevated levels of thrombin-antithrombin complexes and anti-fibrinolytic plasminogen activator inhibitor 1 in their plasma, hypothermia, systemic inflammatory responses and high mortality rate after LPS or TNF-alpha challenge. Propionibacterium acnes treatment reportedly induces both T(h)1 and T(h)17 cell development. Propionibacterium acnes-primed Il12p40(-/-) and Ifngamma(-/-) mice, while not Il17A(-/-) mice, evaded all these symptoms/signs upon LPS or TNF-alpha challenge, indicating essential requirement of IL-12-IFN-gamma axis for the sensitization to LPS and TNF-alpha. Furthermore, IFN-gamma blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN-gamma to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock.
Summary
Regulatory T cells (Treg) have an essential role in maintaining immune tolerance in the gut. The functional CD4+ Treg express the transcription factor forkhead box protein 3 (FoxP3) or a CD25 high in humans. Further, depletion of elevated granulocytes/monocytes by extracorporeal adsorption (GMA) induces immunomodulation in patients with ulcerative colitis (UC). We investigated the impact of GMA on Treg. Thirty-one UC patients, clinical activity index (CAI) 12·1 Ϯ 2·97, refractory to conventional medications including intravenous corticosteroid and 13 healthy controls (HC), were included. Patients received five GMA sessions over 5 weeks. Biopsies from the rectal mucosa and blood samples at baseline and post-GMA were immunostained with anti-CD4/FoxP3 and anti-CD4/CD25 antibodies for immunohistochemistry and flow cytometry. Following GMA, 22 of 31 patients achieved remission (CAI Յ 4, P < 0·01) and their endoscopic activity index decreased from 10·6 Ϯ 2·32 to 4·75 Ϯ 1·48 (P = 0·003).
The circulating CD4+ CD25 high+ Treg level was low and increased markedly in responders (P < 0·02). In the nine non-responders, the baseline CD4 + CD25 high+ Treg level was about 50% of the level in the responders (P < 0·03) or in the HC (P < 0·01), and all nine had to undergo colectomy. Conversely, the number of CD4 + /FoxP3 + mucosal Treg in GMA responders decreased significantly after the fifth GMA session compared with the baseline level (P < 0·05). It is believed that the CD4 + Treg has an essential role in the control of immune pathology in UC patients and a net influx of these cells from the circulation into the mucosa may proceed to suppress inflammation. GMA can impact the circulating as well as the mucosal levels of Treg.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.