title: Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing.
abstract: Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2cub/cub) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2cub/cubmice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2cub/cuband Rhbdf2+/+mice at 0h, 15min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2cub/cubmice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States. Electronic address: vishnu.hosur@jax.org.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Hosur
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Burzenski
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Stearns
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Farley
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Wiles
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, United States. Electronic address: lenny.shultz@jax.org.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
mesh_terms: D000818:Animals; D000975:Antioxidants; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004423:Ear / Q000293:injuries; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; C517507:FcgammaRIIIA protein, mouse; D007074:Immunoglobulin G; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017452:Receptors, IgG; C569468:iRhom2 protein, mouse; D066246:ErbB Receptors