NINJ1: A new player in multiple sclerosis pathogenesis and potential therapeutic target DOI Creative Commons

Yinbin Xu,

Enhao Zhang,

Liangzhe Wei

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 141, P. 113021 - 113021

Published: Aug. 27, 2024

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest potential role nerve injury-induced protein 1 (NINJ1) in pathogenesis. NINJ1, involved cell death and inflammation, may contribute to infiltration activation cells CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during death, leading release mediators further tissue damage. This review explores emerging evidence NINJ1's involvement MS. It discusses how NINJ1 might mediate migration immune across barrier, exacerbate neuroinflammation, participate rupture-related Finally, examines therapeutic strategies targeting improved management. Abbreviations: MS, sclerosis; Central system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis APCs, Antigen-presenting cells; ECs, Endothelial TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear FACS, Fluorescence-activated sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T receptor; ROS, Reactive oxygen species; AP-1, Activator ANG1, Angiopoietin BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase PAK1, p21-activated kinases Rac1, Ras-related C3 botulinum toxin substrate β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor adapter TLR4, Toll-like 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF associated factor 6; TAB2/3, TAK1 binding TAK1, transforming factor-β-activated JNK, c-Jun N-terminal ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor kappa B IκB, NF-κB; NF-κB, nuclear kappa-B; activator ASC, Apoptosis-associated Speck-like containing CARD; NEK7, NIMA-related 7; CREB, cAMP element-binding protein.

Language: Английский

Targeting NINJ1-mediated cell rupture to treat inflammatory diseases DOI Creative Commons

Claire Ju-Eun Hur,

Benjamin E. Steinberg

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Feb. 14, 2025

Abstract Cell death can terminate in plasma membrane rupture to release potent pro-inflammatory intracellular contents thereby contributing inflammatory diseases. is an active process, mediated by the protein ninjurin-1 (NINJ1) pyroptosis, post-apoptosis lysis, ferroptosis, and forms of necrosis. Once activated, NINJ1 clusters into large oligomers within initiate cellular lysis. Recent preclinical studies have demonstrated that inhibiting a new strategy for treating immune-mediated Indeed, both small molecule inhibitors neutralizing antibodies target clustering preserve integrity mitigate disease pathogenesis. In this Perspective , we provide summary current state knowledge recent developments targeting during cell through inhibition treat disease, with focus on liver injury. As these NINJ1-mediated pathways are pivotal maintaining health contribute pathogenesis when dysregulated, discussed broad implications across immunologic basis molecular medicine.

Language: Английский

Citations

1
Multifaceted roles of ninjurin1 in immunity, cell death, and disease DOI Creative Commons
Li Zhu, Yunfei Xu

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 31, 2025

Ninjurin1 (NINJ1) is initially identified as a nerve injury-induced adhesion molecule that facilitates axon growth. It characterized to promote regeneration and mediate the transendothelial transport of monocytes/macrophages associated with neuroinflammation. Recent evidence indicates NINJ1 mediates plasma membrane rupture (PMR) in lytic cell death. The absence or inhibition can delay PMR, thereby mitigating spread inflammation resulting from lysis preventing progression various death-related pathologies, suggesting conserved regulatory mechanism across these processes. Further research elucidated structural basis NINJ1-mediated PMR. Although role PMR established, identity its activating factors implications diseases remain be fully explored. This review synthesizes current knowledge regarding discusses significance therapeutic targeting potential inflammatory diseases, neurological disorders, cancer, vascular injuries.

Language: Английский

Citations

0
NINJ1 in Cell Death and Ferroptosis: Implications for Tumor Invasion and Metastasis DOI Open Access
Ssu-Yu Chen,

Ing-Luen Shyu,

Jen‐Tsan Chi

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 800 - 800

Published: Feb. 26, 2025

NINJ1 was initially recognized for its role in nerve regeneration and cellular adhesion. Subsequent studies have uncovered participation cancer progression, where regulates critical steps tumor metastasis, such as cell migration invasion. More recently, has emerged a multifunctional protein mediating plasma membrane rupture (PMR) several lytic death processes, including apoptosis, necroptosis, pyroptosis. However, ferroptosis-an iron-dependent form of characterized by lipid peroxidation-remained unclear until 2024. Ferroptosis is suppression mechanism that may be particularly relevant to detached metastatic cells. This review explores the invasion focusing on regulation ferroptosis via non-canonical distinct from other deaths. We discuss process implications metastasis. Furthermore, we recent highlighting diverse roles regulation, canonical function PMR modulating intracellular levels glutathione (GSH) coenzyme A (CoA) interaction with xCT anti-porter. Given been associated suppression, elimination treatment-resistant cells, dormancy, NINJ1's modulation presents promising therapeutic target inhibiting Understanding dual promoting or restraining depending context could open avenues novel anti-cancer strategies enhance ferroptotic vulnerability tumors.

Language: Английский

Citations

0
Unraveling the mechanisms of NINJ1-mediated plasma membrane rupture in lytic cell death and related diseases DOI
Jiajia Yang,

Chun Luo,

Kunbo Wang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 309, P. 143165 - 143165

Published: April 15, 2025

Language: Английский

Citations

0
Structural and functional insights of NINJ1 in plasma membrane rupture during cell death DOI Creative Commons

Chehao Lee,

Yuqing Liang,

Li Yang

et al.

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: March 1, 2024

Language: Английский

Citations

2
NINJ1: A new player in multiple sclerosis pathogenesis and potential therapeutic target DOI Creative Commons

Yinbin Xu,

Enhao Zhang,

Liangzhe Wei

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 141, P. 113021 - 113021

Published: Aug. 27, 2024

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest potential role nerve injury-induced protein 1 (NINJ1) in pathogenesis. NINJ1, involved cell death and inflammation, may contribute to infiltration activation cells CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during death, leading release mediators further tissue damage. This review explores emerging evidence NINJ1's involvement MS. It discusses how NINJ1 might mediate migration immune across barrier, exacerbate neuroinflammation, participate rupture-related Finally, examines therapeutic strategies targeting improved management. Abbreviations: MS, sclerosis; Central system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis APCs, Antigen-presenting cells; ECs, Endothelial TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear FACS, Fluorescence-activated sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T receptor; ROS, Reactive oxygen species; AP-1, Activator ANG1, Angiopoietin BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase PAK1, p21-activated kinases Rac1, Ras-related C3 botulinum toxin substrate β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor adapter TLR4, Toll-like 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF associated factor 6; TAB2/3, TAK1 binding TAK1, transforming factor-β-activated JNK, c-Jun N-terminal ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor kappa B IκB, NF-κB; NF-κB, nuclear kappa-B; activator ASC, Apoptosis-associated Speck-like containing CARD; NEK7, NIMA-related 7; CREB, cAMP element-binding protein.

Language: Английский

Citations

2