Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation

被引：61

作者：

Vogelaar, Christina F. ^{[1
,2
]}

Mandal, Shibajee ^{[1
,2
]}

Lerch, Steffen ^{[1
,2
]}

Birkner, Katharina ^{[1
,2
]}

Birkenstock, Jerome ^{[1
,2
]}

Buehler, Ulrike ^{[1
,2
]}

Schnatz, Andrea ^{[3
]}

Raine, Cedric S. ^{[4
]}

Bittner, Stefan ^{[1
,2
]}

Vogt, Johannes ^{[3
]}

Kipnis, Jonathan ^{[5
,6
,7
]}

Nitsch, Robert ^{[8
]}

Zipp, Frauke ^{[1
,2
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Dept Neurol, Focus Program Translat Neurosci FTN, Univ Med Ctr, D-55131 Mainz, Germany

[2] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immunotherapy FZI, Rhine Main Neurosci Network Rmn2, D-55131 Mainz, Germany

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Rhine Main Neurosci Network Rmn2, Inst Microanat & Neurobiol,Focus Program Translat, D-55131 Mainz, Germany

[4] Albert Einstein Coll Med, Dept Pathol, Neuropathol, Bronx, NY 10461 USA

[5] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Gutenberg Res Fellowship Grp Neuroimmunol, Focus Program Translat Neurosci FTN, D-55131 Mainz, Germany

[6] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immunotherapy FZI, Rhine Main Neurosci Network Rmn2, D-55131 Mainz, Germany

[7] Univ Virginia, Sch Med, Dept Neurosci, Ctr Brain Immunol & Glia, Charlottesville, VA 22908 USA

[8] Westfal Wilhelms Univ Munster, Univ Med Ctr, Inst Translat Neurosci, Albert Schweitzer Campus, D-48149 Munster, Germany

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2018年 / 10卷 / 430期

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SPINAL-CORD-INJURY; MULTIPLE-SCLEROSIS; T-CELLS; IN-VIVO; NOGO-A; FUNCTIONAL RECOVERY; NEURITE OUTGROWTH; AXON REGENERATION; NERVOUS-SYSTEM;

D O I：

10.1126/scitranslmed.aao2304

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions.

引用

页数：12