The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury

Sachin P Gadani; James T Walsh; Igor Smirnov; Jingjing Zheng; Jonathan Kipnis

doi:10.1016/j.neuron.2015.01.013

The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury

Neuron. 2015 Feb 18;85(4):703-9. doi: 10.1016/j.neuron.2015.01.013. Epub 2015 Feb 5.

Authors

Sachin P Gadani¹, James T Walsh², Igor Smirnov³, Jingjing Zheng⁴, Jonathan Kipnis⁵

Affiliations

¹ Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: sg8th@virginia.edu.
² Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
³ Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
⁴ Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Institute of Neurosciences, the Fourth Military Medical University, Xi'an, 710032 China.
⁵ Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: kipnis@virginia.edu.

PMID: 25661185
DOI: 10.1016/j.neuron.2015.01.013

Abstract

Inflammation is a prominent feature of CNS injury that heavily influences neuronal survival, yet the signals that initiate and control it remain poorly understood. Here we identify the nuclear alarmin, interleukin (IL)-33, as an important regulator of the innate immune response after CNS injury. IL-33 is expressed widely throughout the healthy brain and is concentrated in white mater due to predominant expression in post-mitotic oligodendrocytes. IL-33 is released immediately after CNS injury from damaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment. Mice lacking IL-33 have impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site. These results demonstrate a novel molecular mediator contributing to immune cell recruitment to the injured CNS and may lead to new therapeutic insights in CNS injury and neurodegenerative diseases.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Animals, Newborn
CX3C Chemokine Receptor 1
Cells, Cultured
Central Nervous System Diseases* / etiology
Central Nervous System Diseases* / immunology
Central Nervous System Diseases* / pathology
Central Nervous System Diseases* / physiopathology
Disease Models, Animal
Female
Gene Expression Regulation / genetics
Gene Expression Regulation / physiology*
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
In Vitro Techniques
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins / genetics
Interleukins / metabolism*
Ki-67 Antigen / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins / metabolism
Neuroglia / metabolism*
Neurons / metabolism
Receptors, Chemokine / genetics
Receptors, Chemokine / metabolism
Receptors, Interleukin / deficiency
Receptors, Interleukin / genetics
Recovery of Function / physiology*
Retinal Ganglion Cells / metabolism
Retinal Ganglion Cells / pathology

Substances

CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins
Ki-67 Antigen
Nerve Tissue Proteins
Receptors, Chemokine
Receptors, Interleukin
enhanced green fluorescent protein
Green Fluorescent Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding