Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ؎ 5% vs. 77 ؎ 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ؎ 450 vs. 255 ؎ 23 g͞g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.

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Neuropathic pain caused by nerve injury or disease remains a major challenge for modern medicine worldwide. Most of the pathogenic mechanisms underlying neuropathic pain are centered on neuronal mechanisms. Accumulating evidence suggests that non-neuronal cells, especially glial cells, also play active roles in the initiation and resolution of pain. The preponderance of evidence has implicated central nervous system (CNS) glial cells, i.e., microglia and astrocytes, in the control of pain. The role of Schwann cells in neuropathic pain remains poorly understood. Schwann cells, which detect nerve injury and provide the first response, play a critical role in the development and maintenance of neuropathic pain. The cells respond to nerve injury by changing their phenotype, proliferating and interacting with nociceptive neurons by releasing glial mediators (growth factors, cytokines, chemokines, and biologically active small molecules). In addition, receptors expressed in active Schwann cells have the potential to regulate different pain conditions. In this review article, we will provide and discuss emerging evidence by integrating recent advances related to Schwann cells and neuropathic pain.

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