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Peer-reviewedCC BY 4.0JCI Insight

Optic nerve regeneration requires the intracellular domain of LIFRα/CD118

  • Qian Jiang1,2
  • Cong Wang1,2
  • Yuerong Ren1,2
  • Peiyun Duan1,2
  • Ke Tian1,2
  • Xiangwei Duan1,2
  • Binghan Cai1,2
  • Changzhong Xu1,2
  • Ke Liu1,2
  • Jian Li3
  • Larry Benowitz4
  • Ningli Wang5
2 more authors
  • Bing Jiang1,2
  • Lili Xie1,2
5 affiliations
  1. 1Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  2. 2Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
  3. 3Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  4. 4Departments of Neurosurgery and Ophthalmology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  5. 5Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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Abstract

Identifying factors that govern the ability of retinal ganglion cells (RGCs) to extend axons is an important step in developing therapies to achieve recovery after optic nerve injury. Here, we report that the intracellular domain of the leukemia inhibitory factor receptor (LIFR/CD118) is essential for mature RGCs’ ability to regenerate injured axons independent of the cognate ligand (LIF) and other therapies. Overexpression of LIFR in adult RGCs induces neurite outgrowth in cultured RGCs and axon regeneration in vivo while strongly amplifying RGCs’ response to LIF itself and to unrelated growth factors. Conversely, downregulation of LIFR strongly suppresses the pro-regenerative effects of PTEN knockdown and other potent stimuli. LIFR modulation alters the constitutive activity of the MAPK pathway, in contrast to LIF itself, which primarily activates pSTAT3. The extracellular domain–truncated LIFR construct retains substantial pro-regenerative activity, whereas mutation of intracellular signaling motifs reduces the full regenerative effect of LIFR. Together, these findings identify LIFR as a key cell-autonomous regulator of optic nerve regeneration in mature RGCs.

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Cite

BibTeXRIS
BibTeX
@article{jiang2026optic,
  title = {{Optic nerve regeneration requires the intracellular domain of LIFRα/CD118}},
  author = {Qian Jiang and Cong Wang and Yuerong Ren and Peiyun Duan and Ke Tian and Xiangwei Duan and Binghan Cai and Changzhong Xu and Ke Liu and Jian Li and Larry Benowitz and Ningli Wang and Bing Jiang and Lili Xie},
  journal = {JCI Insight},
  year = {2026},
  month = sep,
  doi = {10.1172/jci.insight.202223},
  url = {https://doi.org/10.1172/jci.insight.202223},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Optic nerve regeneration requires the intracellular domain of LIFRα/CD118
AU  - Qian Jiang
AU  - Cong Wang
AU  - Yuerong Ren
AU  - Peiyun Duan
AU  - Ke Tian
AU  - Xiangwei Duan
AU  - Binghan Cai
AU  - Changzhong Xu
AU  - Ke Liu
AU  - Jian Li
AU  - Larry Benowitz
AU  - Ningli Wang
AU  - Bing Jiang
AU  - Lili Xie
PY  - 2026
DA  - 2026/09/01
JO  - JCI Insight
DO  - 10.1172/jci.insight.202223
UR  - https://doi.org/10.1172/jci.insight.202223
AB  - Identifying factors that govern the ability of retinal ganglion cells (RGCs) to extend axons is an important step in developing therapies to achieve recovery after optic nerve injury. Here, we report that the intracellular domain of the leukemia inhibitory factor receptor (LIFR/CD118) is essential for mature RGCs’ ability to regenerate injured axons independent of the cognate ligand (LIF) and other therapies. Overexpression of LIFR in adult RGCs induces neurite outgrowth in cultured RGCs and axon regeneration in vivo while strongly amplifying RGCs’ response to LIF itself and to unrelated growth factors. Conversely, downregulation of LIFR strongly suppresses the pro-regenerative effects of PTEN knockdown and other potent stimuli. LIFR modulation alters the constitutive activity of the MAPK pathway, in contrast to LIF itself, which primarily activates pSTAT3. The extracellular domain–truncated LIFR construct retains substantial pro-regenerative activity, whereas mutation of intracellular signaling motifs reduces the full regenerative effect of LIFR. Together, these findings identify LIFR as a key cell-autonomous regulator of optic nerve regeneration in mature RGCs.
SN  - 2379-3708
ER  -