Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis

Weber, Georg F.; Chousterman, Benjamin; He, Shasha; Fenn, Ashley M.; Nairz, Manfred; Anzai, Atsushi; Brenner, Thorsten; Uhle, Florian; Iwamoto, Yoshiko; Robbins, Clinton S.; Noiret, Lorette; Maier, Sarah; Zönnchen, Tina; Rahbari, Nuh N.; Schölch, Sebastian; Ameln, Anne Klotzsche von; Chavakis, Triantafyllos; Weitz, Jürgen; Hofer, Stefan; Weigand, Markus A.; Nahrendorf, Matthias; Weissleder, Ralph; Świrski, Filip K.

doi:10.1126/science.aaa4268

Cited by 294 publications

(272 citation statements)

References 35 publications

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“…36,37 Recently, it was described that IL-3 promotes the production of inflammatory monocytes and neutrophils in a sepsis model. 38 Our data also show significantly increased numbers of monocytes and neutrophils in the spleen and/or bone marrow of mice treated with IL-3. The numbers of mast cells and dendritic cells were not significantly altered in the spleen, kidney, and bone marrow, when 18-week-old MRL/lpr mice were treated for 6 days with anti-IL-3 (50 μg/day) or IL-3 (200 ng/day) (data not shown).…”

Section: Discussionsupporting

confidence: 67%

IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

Renner

Hermann

Schmidbauer

et al. 2015

Kidney International

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MRL/lpr mice develop a spontaneous autoimmune disease that closely resembles human systemic lupus erythematosus (SLE) with DNA autoantibodies, hypergammaglobulinemia, immune complex glomerulonephritis, and systemic vasculitis. Little is known about the role of IL-3 in SLE. In order to study this we analyzed the expression of IL-3 in murine lupus and determined whether blockade of IL-3 with a monoclonal antibody or injection of recombinant IL-3 affects lupus nephritis in MRL/lpr mice. During disease progression IL-3 levels were increased in the plasma and in the supernatant of cultured splenocytes from MRL/lpr mice. Administration of IL-3 aggravated the disease with significantly higher renal activity scores, more renal fibrosis, and more glomerular leukocyte infiltration and IgG deposition. Blockade of IL-3 significantly improved acute and chronic kidney damage, reduced the glomerular infiltration of leukocytes and the glomerular deposition of IgG, and decreased the development of renal fibrosis. Furthermore, DNA autoantibody production, proteinuria, and serum creatinine levels were significantly lower in the anti-IL-3 group. Thus, IL-3 plays an important role in the pathogenesis of SLE and the progression of lupus nephritis. Hence, blockade of IL-3 may represent a new strategy for treatment of lupus nephritis.

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Section: Discussionsupporting

confidence: 67%

IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

Renner

Hermann

Schmidbauer

et al. 2015

Kidney International

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“…In a proof-of-concept study, we showed that high IL-3 levels in septic patients are associated with high mortality. 17 A recent study further confirmed the role of IL-3 in the immune regulation and potential response to corticosteroids during sepsis. 19 Translating this discovery into a clinically viable test, however, requires a fast, easy-to-use platform that could overcome the long assay time (5–8 hours) and complexity of a standard enzyme-linked immunosorbent assay (ELISA).…”

Section: Introductionmentioning

confidence: 75%

Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis

et al. 2018

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Sepsis is an often fatal condition that arises when the immune response to an infection causes widespread systemic organ injury. A critical unmet need in combating sepsis is the lack of accurate early biomarkers that produce actionable results in busy clinical settings. Here, we report the development of a point-of-care platform for rapid sepsis detection. Termed IBS (integrated biosensor for sepsis), our approach leverages i) the newly-found pathophysiological role of cytokine interleukin-3 (IL-3) in early sepsis, and ii) a hybrid magneto-electrochemical sensor for IL-3 detection. The developed platform produces test results within 1 hour from native blood samples, and detects IL-3 at a sensitivity of <10 pg/mL; this performance is >5-times faster and >10-times more sensitive than a current gold standard, enzyme-linked immunoadsorbent assay. Using clinical samples, we show that high plasma IL-3 levels are associated with high organ failure rate and thus greater risk of mortality, confirming the potential of IL-3 as an early diagnostic biomarker. Compact and fast, the IBS platform can be readily integrated into clinical workflows, enabling timely diagnosis and proactive treatment of sepsis.

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“…In addition, the roles that cytokines and inflammatory pathways play in sepsis pathogenesis are gradually being elucidated [48,49]. The application of bioinformatics and computerized mathematical models has also contributed to greater knowledge of the pathogenesis of sepsis [27,50].…”

Section: Pathogenesis Of Sepsismentioning

confidence: 99%

“…In addition to anti-TNF therapy, several research efforts have been dedicated to investigating the potential of therapies targeting proinflammatory cytokines in sepsis. Recently, Weber et al [49 ]reported on the role of IL-3 in sepsis and that IL-3 deficiency protects mice from sepsis. This adds to reports that blockade of high-mobility group box 1 (HMGB1) [83], IL-17 [84], IL-1 [85] and many other cytokines was protective in experimental models of sepsis.…”

Section: Targeting Inflammationmentioning

confidence: 99%

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine

Okeke

Uzonna²

2016

J Innate Immun

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In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. However, numerous efforts aimed at targeting the proinflammatory cytokine network have been largely unsuccessful and the search for novel potential therapeutic targets continues. Recent studies provide compelling evidence that dysregulated anti-inflammatory responses may also contribute to sepsis mortality. Our previous studies on the role of regulatory T cells and phosphoinositide 3-kinases in sepsis highlight immunological approaches that could be explored for sepsis therapy. In this article, we review the current and emerging concepts in sepsis, highlight novel potential therapeutic targets and immunological approaches for sepsis treatment and propose a biphasic treatment approach for management of the condition.

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Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis

Cited by 294 publications

References 35 publications

IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine

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