{"doi":"10.1016/j.ajpath.2024.02.002","title":"The Unrecognized Role of Ninjurin 2 in Inflammation, Metabolism, and Pyroptosis","abstract":"Ninjurin family proteins are a group of double transmembrane proteins that are up-regulated in both dorsal root ganglion neurons and Schwann cells following nerve injury.1Araki T. Milbrandt J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth.Neuron. 1996; 17: 353-361Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar,2Araki T. Milbrandt J. Ninjurin2, a novel homophilic adhesion molecule, is expressed in mature sensory and enteric neurons and promotes neurite outgrowth.J Neurosci. 2000; 20: 187-195Crossref PubMed Google Scholar The nerve injury–induced protein 1 (ninjurin 1; NINJ1) and NINJ2 are two homologous ninjurin family proteins in human beings. NINJ1 and NINJ2 are located on different chromosomes and have different expression patterns. For instance, NINJ1 is ubiquitously expressed in various epithelial tissues, whereas NINJ2 shows high expression in hematopoietic and lymphatic tissues.3Liu K. Wang Y. Li H. The role of Ninjurin1 and its impact beyond the nervous system.Dev Neurosci. 2020; 42: 159-169Crossref PubMed Scopus (7) Google Scholar,4Sorosina M. Peroni S. Mascia E. Santoro S. Osiceanu A.M. Ferre L. Clarelli F. Giordano A. Cannizzaro M. Martinelli Boneschi F. Filippi M. Esposito F. Involvement of NINJ2 protein in inflammation and blood-brain barrier transmigration of monocytes in multiple sclerosis.Genes (Basel). 2022; 13: 1946Crossref Scopus (0) Google Scholar NINJ1 and NINJ2 have also been shown to belong to cell adhesion molecules that play a critical role in a variety of physiological and pathologic processes, including inflammation, angiogenesis, and tumorigenesis.3Liu K. Wang Y. Li H. The role of Ninjurin1 and its impact beyond the nervous system.Dev Neurosci. 2020; 42: 159-169Crossref PubMed Scopus (7) Google Scholar,4Sorosina M. Peroni S. Mascia E. Santoro S. Osiceanu A.M. Ferre L. Clarelli F. Giordano A. Cannizzaro M. Martinelli Boneschi F. Filippi M. Esposito F. Involvement of NINJ2 protein in inflammation and blood-brain barrier transmigration of monocytes in multiple sclerosis.Genes (Basel). 2022; 13: 1946Crossref Scopus (0) Google Scholar As double transmembrane proteins, NINJ1 and NINJ2 consist of two extracellular domains, two transmembrane domains, and a cytoplasmic domain.1Araki T. Milbrandt J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth.Neuron. 1996; 17: 353-361Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar,2Araki T. Milbrandt J. Ninjurin2, a novel homophilic adhesion molecule, is expressed in mature sensory and enteric neurons and promotes neurite outgrowth.J Neurosci. 2000; 20: 187-195Crossref PubMed Google Scholar Both NINJ1 and NINJ2 were originally identified to play important roles in nerve injury response and neuronal function by promoting neurite outgrowth and facilitating neuronal regeneration following nerve injury, which is why they were named nerve injury–induced proteins.1Araki T. Milbrandt J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth.Neuron. 1996; 17: 353-361Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 2Araki T. Milbrandt J. Ninjurin2, a novel homophilic adhesion molecule, is expressed in mature sensory and enteric neurons and promotes neurite outgrowth.J Neurosci. 2000; 20: 187-195Crossref PubMed Google Scholar, 3Liu K. Wang Y. Li H. The role of Ninjurin1 and its impact beyond the nervous system.Dev Neurosci. 2020; 42: 159-169Crossref PubMed Scopus (7) Google Scholar Interestingly, recent studies have shown that NINJ1 and NINJ2 play a role in different physiological and pathologic processes in many different tissues in addition to the neuronal system. For instance, NINJ1 has been reported to be involved in inflammation, immune regulation, cell death, muscle and bone homeostasis, angiogenesis, and tumorigenesis.3Liu K. Wang Y. Li H. 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