Sepsis impedes EAE disease development and diminishes autoantigen-specific naïve CD4 T cells
Abstract
Evaluation of sepsis-induced immunoparalysis has highlighted how decreased lymphocyte number/function contribute to worsened infection/cancer. Yet an interesting contrast exists with autoimmune disease development, wherein diminishing pathogenic effectors may benefit the post-septic host. Within this framework the impact of cecal ligation and puncture (CLP)-induced sepsis on the development of experimental autoimmune encephalomyelitis (EAE) was explored. Notably, CLP mice have delayed onset and reduced disease severity, relative to sham mice. Reduction in disease severity was associated with reduced number, but not function, of autoantigen (MOG)-specific pathogenic CD4 T cells in the CNS during disease and draining lymph node during priming. Numerical deficits of CD4 T cell effectors are associated with the loss of MOG-specific naive precursors. Critically, transfer of MOG-TCR transgenic (2D2) CD4 T cells after, but not before, CLP led to EAE disease equivalent to sham mice. Thus, broad impairment of antigenic responses, including autoantigens, is a hallmark of sepsis-induced immunoparalysis.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (AI114543)
- Vladimir P Badovinac
National Institute of Allergy and Infectious Diseases (T32AI007511)
- Isaac J jensen
National Institute of Allergy and Infectious Diseases (T32AI007485)
- Isaac J jensen
National Institute of Allergy and Infectious Diseases (T32AI007485)
- Samantha N Jensen
National Institute of Allergy and Infectious Diseases (AI137075-S1)
- Samantha N Jensen
National Cancer Institute (T32CA009138)
- Frances V Sjaastad
National Institute of Allergy and Infectious Diseases (T32AI007313)
- Frances V Sjaastad
National Institute of General Medical Sciences (1R35134880)
- Vladimir P Badovinac
National Institute of Allergy and Infectious Diseases (AI147064)
- Vladimir P Badovinac
National Institute of General Medical Sciences (GM113961)
- Vladimir P Badovinac
National Institute of General Medical Sciences (GM134880)
- Vladimir P Badovinac
National Institute of General Medical Sciences (GM115462)
- Thomas S Griffith
National Institute of Allergy and Infectious Diseases (AI137075)
- Ashutosh K Mangalam
U.S. Department of Veterans Affairs (I01BX001324)
- Thomas S Griffith
National Institute of Environmental Health Sciences (P30 ES005605)
- Katherine N Gibson-Corley
- Ashutosh K Mangalam
National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK054759)
- Katherine N Gibson-Corley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Urszula Krzych, Walter Reed Army Institute of Research, United States
Ethics
Animal experimentation: Experimental procedures using mice were approved by University of Iowa Animal Care and Use Committee under ACURF protocol number 9101915. The experiments performed followed Office of Laboratory Animal Welfare guidlines and PHS policy on Humane Care and Use of Laboratory Animals. Euthansia was performed by cervical dislocation or carbon dioxide asphyxiation.
Version history
- Received: February 6, 2020
- Accepted: November 15, 2020
- Accepted Manuscript published: November 16, 2020 (version 1)
- Version of Record published: December 7, 2020 (version 2)
Copyright
© 2020, jensen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,404
- views
-
- 202
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
-
- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.