Menu

Close

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

Themistoklis M. Tsarouchas, Daniel Wehner, Leonardo Cavone, Tahimina Munir, Marcus Keatinge, Marvin Lambertus, Anna Underhill, Thomas Barrett, Elias Kassapis, Nikolay Ogryzko, Yi Feng, Tjakko J. van Ham, Thomas Becker, Catherina G. Becker

Preprint posted on May 28, 2018 https://www.biorxiv.org/content/early/2018/05/28/332197.1

To regenerate, or not to regenerate? Researchers shed light on key immune mechanisms and spatiotemporal dynamics that orchestrate spinal cord regeneration in zebrafish.

Selected by Shikha Nayar

Context and Background

The zebrafish is a well-recognized model system used for vertebrate regeneration research, including, but not limited to, heart, liver, brain, fin, and spinal cord regeneration1. The observation that a robust immune response is elicited upon spinal cord injury is not a novel one2; yet key mechanisms, cell types, and spatiotemporal dynamics are still to be elucidated in a vertebrate system. Macrophages, neutrophils, and microglia are fundamental innate immune cell types that elicit an immediate immune response upon injury, yet their dynamics are rapid and thus difficult to study. The zebrafish embryo is a unique model system as it only possesses a functional innate, but not adaptive, immune system at embryonic and larval stages. This makes it highly effective for dissecting mechanisms of innate immune cell infiltration and axon growth during spinal cord regeneration in vivo (Figure 1).

Figure 1. Schematic of multistep process of spinal cord regeneration in zebrafish (Figure 1a from Mokalled et al., 2016).

 

Key findings

How do infiltrating immune cells control cytokine dynamics to promote mechanisms of regeneration? In this preprint, Tsarouchas et al use the zebrafish embryo to show that peripheral macrophages control a delicate balance of pro-regenerative and pro-inflammatory cytokine production to promote successful axon regeneration. They show that macrophages, but not neutrophils, are necessary for the regulation and maintenance of this cytokine balance. They conclude that an induction of tnfα but reduction of il1β is necessary and sufficient to sustain successful axon regeneration through development. Importantly, the tight spatiotemporal control of cytokine induction was key for long-term regenerative success; early induction of a pro-inflammatory response, but a switch to an anti-inflammatory response after 24 hours is needed for effective regeneration. Notably, macrophage mutants were unable to switch between these biphasic cytokine states, resulting in unsuccessful axon regeneration.

 

Importance of this paper

The textbook view in immunology is that sustained induction of pro-inflammatory cytokines, such as tnfα, is responsible for chronic injury and a failure to elicit repair responses. This study importantly challenges this dogma by dissecting the dynamics of cytokine production through injury and development, to show that appropriate and timely induction of pro-inflammatory cytokines can in fact play a key role in repair. Not only will these findings inform future directions in regeneration research, but they could shape our view of immune dynamics in other disease models, such as Inflammatory Bowel Disease, that also currently view cytokines like tnfα as detrimental to healing and repair processes.

 

Open questions

The authors do discuss the intricacies of axon bridging as a potential therapeutic strategy, as shown in neutrophil-depleted mutants, however this idea could be further explored. How does axon bridging naturally take place, and what immune mechanisms are necessary to orchestrate the process? How do patients with defects in innate immune populations such as neutrophils and macrophages, resolve injury induced by noxious stimuli? What are the cytokine levels and spatiotemporal dynamics in patients with dysfunctional macrophages? Could these patients be targeted for “personalized cytokine induction”? Further, this study is carried out with the goal of dissecting primarily innate immune mechanisms of repair; how would these dynamics be altered with the emergence of a functional adaptive immune system in vivo later in development? Investigating the intersection of immunology, regeneration, and the use of novel model systems, will help us answer these questions and provide new avenues for translational approaches in spinal cord regeneration.

 

References

  1. Gemberling A, Bailey TJ, Hyde DR, Poss KD. The zebrafish as a model for complex tissue regeneration. Trends in Genetics. 2013;29(11):611-620. doi:10.1016/j.tig.2013.07.003.
  2. Mokalled MH, Patra C, Dickson AL, Endo T, Stainier DYR, Poss KD. Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science.  2016;6312(354):630-634. doi:10.1126/science.aaf2679.
  3. Trivedi A, Olivas AD, Noble-Haeusslein LJ. Inflammation and Spinal Cord Injury: Infiltrating Leukocytes as Determinants of Injury and Repair Processes. Clinical neuroscience research. 2006;6(5):283-292. doi:10.1016/j.cnr.2006.09.007.

Tags: inflammation, macrophages, regeneration, spinal cord, zebrafish

Posted on: 30th July 2018

Read preprint (No Ratings Yet)




  • Author's response

    Thomas Becker, Catherina Becker, Themistoklis Tsarouchas shared

    Shikha makes some very good points on the complexity of regeneration in her discussion of our study. We were surprised to find such a high level of complex tissue interactions of immune and other cell types already in this “simple” larval zebrafish system during spinal cord regeneration. We hope that the excellent optical and genetic accessibility of this system will allow us to discover important principles of successful spinal cord repair with translational relevance.

    Have your say

    Your email address will not be published. Required fields are marked *

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    LADL: Light-activated dynamic looping for endogenous gene expression control

    Mayuri Rege, Ji Hun Kim, Jacqueline Valeri, et al.



    Selected by Ivan Candido-Ferreira

    Quantitative, real-time, single cell analysis in tissue reveals expression dynamics of neurogenesis

    Cerys S Manning, Veronica Biga, James Boyd, et al.



    Selected by Teresa Rayon

    The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila



    Selected by Clarice Hong

    1

    Optogenetic dissection of mitotic spindle positioning in vivo

    Lars-Eric Fielmich, Ruben Schmidt, Daniel J Dickinson, et al.



    Selected by Angika Basant

    1

    Excitable RhoA dynamics drive pulsed contractions in the early C. elegans embryo.

    Jonathan B Michaux, Francois B Robin, William M McFadden, et al.



    Selected by Sundar Naganathan

    A transition from SoxB1 to SoxE transcription factors is essential for progression from pluripotent blastula cells to neural crest cells

    Elsy Buitrago-Delgado, Elizabeth Schock, Kara Nordin, et al.



    Selected by Amanda Haage

    Moving beyond P values: Everyday data analysis with estimation plots

    Joses Ho, Tayfun Tumkaya, Sameer Aryal, et al.



    Selected by Gautam Dey

    1

    JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

    Daniel Hu, Heinrich Jasper



    Selected by Maiko Kitaoka

    ER-to-Golgi trafficking of procollagen in the absence of large carriers.

    Janine McCaughey, Nicola Stevenson, Stephen Cross, et al.



    Selected by Gautam Dey

    1

    Mechanosensitive binding of p120-Catenin at cell junctions regulates E-Cadherin turnover and epithelial viscoelasticity

    K. Venkatesan Iyer, Romina Piscitello-Gómez, Frank Jülicher, et al.



    Selected by Ivana Viktorinová

    A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion

    Richard W Naylor, Alan J Davidson



    Selected by Giuliana Clemente

    1

    An intrinsic cell cycle timer terminates limb bud outgrowth

    Joseph Pickering, Kavitha Chinnaiya, Constance A Rich, et al.



    Selected by Ashrifia Adomako-Ankomah

    1

    Fbxw7 is a critical regulator of Schwann cell myelinating potential

    Breanne L Harty, Fernanda Coelho, Sarah D Ackerman, et al.



    Selected by Yen-Chung Chen

    Kinetic sculpting of the seven stripes of the Drosophila even-skipped gene

    Augusto Berrocal, Nicholas C Lammers, Hernan G Garcia, et al.



    Selected by Erik Clark

    TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila.

    Byoungchun Lee, Elizabeth C Barretto, Savraj S Grewal



    Selected by Sarah Bowling

    The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization

    Sarah Herberg, Krista R Gert, Alexander Schleiffer, et al.



    Selected by James Gagnon

    Also in the genetics category:

    The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila



    Selected by Clarice Hong

    1

    Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

    Themistoklis M. Tsarouchas, Daniel Wehner, Leonardo Cavone, et al.



    Selected by Shikha Nayar

    1

    JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

    Daniel Hu, Heinrich Jasper



    Selected by Maiko Kitaoka

    Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions

    Summer B. Thyme, Lindsey M. Pieper, Eric H. Li, et al.



    Selected by Daniel Grimes

    Super-Mendelian inheritance mediated by CRISPR/Cas9 in the female mouse germline

    Hannah A. Grunwald, Valentino M. Gantz, Gunnar Poplawski, et al.



    Selected by Rebekah Tillotson

    1

    Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects

    Gist H. Farr III, Kimia Imani, Darren Pouv, et al.



    Selected by Hannah Brunsdon

    A robust method for transfection in choanoflagellates illuminates their cell biology and the ancestry of animal septins

    David Booth, Heather Middleton, Nicole King



    Selected by Maya Emmons-Bell

    SWI/SNF remains localized to chromatin in the presence of SCHLAP1

    Jesse R Raab, Keriayn N Smith, Camarie C Spear, et al.



    Selected by Carmen Adriaens

    1

    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.



    Selected by Andreas van Impel

    1

    Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

    Jovany Jeomar Franco, Youmna Maryline Atieh, Chase Dallas Bryan, et al.



    Selected by Helen Weavers

    Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

    Dirk Hubmacher, Stetson Thacker, Sheila M Adams, et al.



    Selected by Alberto Rosello-Diez

    Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ)

    Scott J Callahan, Stephanie Tepan, Yan M Zhang, et al.



    Selected by Hannah Brunsdon

    1

    PDX Finder: A Portal for Patient-Derived tumor Xenograft Model Discovery

    Nathalie Conte, Jeremy Mason, Csaba Halmagyi, et al.



    Selected by Carmen Adriaens

    Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

    Jacob Daane, Jennifer Lanni, Ina Rothenberg, et al.



    Selected by Alberto Rosello-Diez

    1

    Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of cell division, differentiation, and loss

    Judy Martin, Erin Nicole Sanders, Paola Moreno-Roman, et al.



    Selected by Natalie Dye

    F-actin patches nucleated on chromosomes coordinate capture by microtubules in oocyte meiosis

    Mariia Burdyniuk, Andrea Callegari, Masashi Mori, et al.



    Selected by Binyam Mogessie

    Also in the immunology category:

    Precise tuning of gene expression output levels in mammalian cells

    Yale S. Michaels, Mike B Barnkob, Hector Barbosa, et al.



    Selected by Tim Fessenden

    1

    Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

    Themistoklis M. Tsarouchas, Daniel Wehner, Leonardo Cavone, et al.



    Selected by Shikha Nayar

    1

    A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

    Yuxiao Wang, Walter Huynh, Taylor Skokan, et al.



    Selected by Nicola Stevenson

    Human macrophages survive and adopt activated genotypes in living zebrafish

    Colin D. Paul, Alexus Devine, Kevin Bishop, et al.



    Selected by Giuliana Clemente

    1

    Single-cell Map of Diverse Immune Phenotypes Driven by the Tumor Microenvironment

    Elham Azizi, Ambrose J. Carr, George Plitas, et al.



    Selected by Tim Fessenden

    Bacteriophage cooperation suppresses CRISPR-Cas3 and Cas9 immunity

    Adair L Borges, Jenny Y Zhang, MaryClare Rollins, et al.

    AND

    Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity

    Mariann Landsberger, Sylvain Gandon, Sean Meaden, et al.



    Selected by Fillip Port

    Galleria mellonella as an Insect Model for P. destructans, the Cause of White-Nose Syndrome in Bats

    Chapman N Beekman, Lauren Meckler, Eleanor Kim, et al.



    Selected by Heath MacMillan

    Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets

    Matthew H Bakalar, Aaron M Joffe, Eva Schmid, et al.



    Selected by Tim Fessenden
    Close