The spinal cord, which is part of the central nervous system, has been considered a typical example of an organ in which regeneration is difficult. However, since the report of recovery of function in a spinal cord injury (SCI) model as a result of cell transplantation of rat-fetus-derived neural stem/progenitor cells (NS/PCs), stem cell transplantation therapy has attracted great hope of restoring and replenishing lost neurons and glia. In recent years induced pluripotent stem (iPS) cells that possess embryonic stem (ES)-cell-like pluripotency and proliferative capacity have been produced by introducing several different genes into somatic cells. Rapid progress is currently being made in research on iPS cells with the aim of enabling cell transplantation therapy, and reports of the development of methods of inducing human iPS cells to differentiate into a variety of somatic cells and cases of treatment of murine models with mouse iPS cells have appeared one after another. However, when viewed from a safety standpoint, problems that arise because ES cells and iPS cells are both pluripotent stem cells and many problems unique to iPS cells, which have been artificially reprogrammed, still remain unresolved, and there is a desire for further progress in research. In this paper we outline these issues and report the latest findings in regard to application to the treatment of spinal cord injury.

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Nearly two decades have passed since our discovery of the prototypic chemokines, a neutrophil chemotactic factor interleukin 8 (IL 8, CXCL8) and monocyte chemotactic factor MCAF/MCP-1 (CCL2) at the National Cancer Institute, USA. The characterization of chemokines has revealed the molecular mechanisms underlying specific leukocyte subset infiltration into inflammatory tissues, previously a long-standing enigma in inflammation research. In this review we briefly recount the chronology of chemokine research, then overview chemokine receptor signal transduction systems, chemokines in inflammation and immunity, chemokines in HIV infection and cancer, and the current status of therapeutic approaches targeting chemokines and their receptors.

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Cells can be reprogrammed to assume a different fate in vitro. Oct3/4, Sox2, and Klf4 have been used to direct cells to a pluripotent state. These induced pluripotent stem (iPS) cells, which are able to differentiate into any cell type, may provide a novel the-rapeutic avenue for a wide range of disorders. Photoreceptors or retinal pigment epithelia derived from patient iPS cells, for example, may be useful in transplantation therapy for retinal degenerative diseases, and in vitro disease models and drug screening. Recent evidence, however, has revealed significant differences between embryonic stem (ES) cells and iPS cells. iPS cells have helped elucidate the underpinnings of pluripotency, in particular similarities and differences among mouse ES cells, human ES cells, and epiblast stem cells. Intriguingly, cellular plasticity suggests that a specific set of factors could potentially convert somatic cells directly to retinal progenitors or retinal cells. Cellular reprogramming methodologies should markedly contribute to both our understanding of retinal degenerative diseases and the development of novel therapies, including cell transplantation and new drugs.

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Autoinflammatory diseases have recently been recognized as diseases characterized by systemic inflammation mediated by abnormalities in the molecules of the innate immune system. Clinical features of the systemic onset juvenile idiopathic arthritis (sJIA), the most common rheumatic disease in Japan, mimic those of autoinflammatory disease. In addition, a large number of evidence indicates the pathogenesis of sJIA to be closely associated with abnormalities in the innate immune system rather than with the classic autoimmune system. Based on these findings, a consensus is now emerging that sJIA may be a autoinflammatory disease. In order to deepen our understanding of human innate immunity, and to offer more targeted therapies for patients with sJIA, further studies on the genetics and molecular pathophysiology of sJIA and autoinflammatory diseases are essential.

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Sporadic early-onset sarcoidosis (EOS) and familial Blau syndrome (BS) form a distinct set of autoinflammatory diseases, both of which onset in infancy and show a clinical triad of dermatitis, arthritis and uveitis histologically composed of noncaseating epithelioid cell granuloma. The responsible gene for EOS/BS is NOD2, encoding an intracellular receptor for muramyl dipeptide (MDP), the common component of bacterial cell wall peptidoglycan. The gain-of-function NOD2 mutations with MDP-independent basal NF-κB activation cause EOS/BS, while its loss-of-function mutations with impaired MDP-dependent NF-κB activation are associated with Crohn's disease and a part of sarcoidosis. As the result of analyzing genotype-phenotype relationship of Japanese EOS/BS cases, somewhat positive correlation was recognized between mutant NOD2-causing basal NF-κB activation and clinical severity, especially of ocular complications. Role of the basal NF-κB activation in monocytes has also been suggested by an inhibitory effect of thalidomide on ex vivo giant cell formation from EOS/BS patients' monocytes. Analysis of mutant NOD2-introduced human monocytic THP-1 cells, as well as the patients' samples, would provide further detailed molecular mechanisms of EOS/BS pathogenesis, in which a single point missense mutation causes a distinct pathological change forming epithelioid cell granuloma.

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Autoinflammatory diseases were initially assigned to the hereditary recurrent fevers that were characterized by unprovoked episodes of inflammation without antigen-specific T cells or high titers of auto-antibodies, in contrast to the autoimmune diseases in which acquired immunity played an essential role. Except for Blau syndrome and early-onset sarcoidosis that are associated with granuloma due to NOD2 mutations and classified as NF-κB activation disorders, the major types of autoinflammatory diseases are defined as IL-1β activating disorders or inflammasomopathies. This is based on accumulating evidence for the efficacy of anti-IL-1 therapy. These diseases include intrinsic cryopyrin-associated periodic syndrome (CAPS), extrinsic familial Mediterranean fever, hyper IgD syndrome, pyogenic sterile arthritis pyoderma gangrenosum and acne syndrome, and deficiency of an IL-1 receptor antagonist. Knowledge obtained from these autoinflammatory disorders should also be pertinent to a number of common disorders. For example, neutrophil migration is observed in autoinflammatory CAPS and common inflammatory keratoses represented by psoriasis. Abnormal regulation of the innate immune response and Th17 cell differentiation via IL-1 signaling may be associated with the molecular pathogenesis of these conditions.

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Various recent studies reveal that many autoinflammatory syndromes result from inflammasome related protein abnormality. Some inflammasomes closely correlate with caspase 1. Caspase 1 is a key molecule for activation of IL-1β, which is responsible for induction and augmentation of inflammation. Inflammatory cytokines, including IL-1β, are necessary for T_H17 differentiation from T_H0 cell. T_H17 cells were recently reported to play major roles in autoantibody production. In this point of view, inflammasome inducing inflammation participates in prominent roles both in autoinflammatory syndromes and autoimmunity. On the other hand, non-immunological ischemic injury deeply correlates with immunological reaction in kidney transplantation. Inflammation would share significant part both in non-immunological tissue destruction and immunological reaction of rejection in kidney transplantation. Inflammatory cytokines, including IL-1β, and chemokines are key regulators in progression of inflammatory reaction in ischemic kidney injury. Our data indicate that specific chemokines or chemokine receptors participate in specific pathologic changes at specific time points in the injury. One of some molecules, which work for these pathological changes would be new therapeutic targets for transplantation.

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α-Lipoic acid (LA) is a cofactor functioning in four multienzymes: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, and the glycine cleavage enzyme systems. In each enzyme, LA is covalently bound to the ε-amino group of lysine residues. LA has been used as a medicine for treating diabetic condition in Europe and is also currently a popular supplement resource, and thus the metabolic fate after orally intake of LA attracts much attention whether externally administered LA is incorporated into protein bound form because large fraction of administered dose is not fully explained yet. Lipoamidase is the enzyme catalyzing formation and breakage of amide bond between LA and lysine ε-amino groups in the protein and thus is expected to play critical role in LA metabolism and function. In order to know how the enzyme lipoamidase is involved in the fate of LA in the body, a simple assay method is requested for determining lipoamidase activity in tissues. The method using simple HPLC detection of newly synthesized fluorescent substrate, dansyl-α-lipoyllysine, is discussed together with other previously reported methods.

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The transient receptor potential vanilloid-1 (TRPV1) cation channel is a receptor that is activated by heat, acidosis and a variety of chemicals, including capsaicin. With these properties, TRPV1 has emerged as a polymodal nocisensor of nociceptive afferent neurons. As many proalgesic pathways converge on TRPV1 and it is upregulated and sensitized by inflammation and injury, TRPV1 is thought to be a central transducer of hyperalgesia and a prime target for the pharmacological control of pain. However, there is conflicting evidence to date as to whether TRPV1 agonists promote or inhibit inflammation. We recently demonstrated that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel TRPV1 agonist, inhibits tumor necrosis factor-α production through the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms of kidney injury, lung inflammation, arthritis and encephalomyelitis in disease models. These results suggest that TRPV1 agonists may act in an anti-inflammatory manner in vivo in certain inflammatory diseases.

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Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, yet the roles of specific lymphocyte subpopulations and cytokines in stroke remain to be clarified. We demonstrated that IL-23 and IL-17, rather than IFN-γ, play pivotal roles in the evolution of brain infarction. IL-23 was produced from infiltrated macrophages in the immediate phase of brain ischemia; thereafter, IL-17-producing T lymphocytes were infiltrated into the ischemic brain tissue in the delayed phase. IL-17 was mostly produced in γδT lymphocytes, and was dependent on IL-23. We discovered that not only IL-23 but also IL-17 deficiency prevented neural cell death in the delayed phase of ischemic brain injury. We also demonstrated that FTY720 administration, which blocked T cell infiltration into the brain, suppressed ischemic brain injury. Furthermore, the depletion of γδT cells also attenuated ischemic brain damages. Therefore, we propose that cerebral T lymphocytes, including γδT lymphocytes, be considered as new therapeutic targets in a novel neuroprotective strategy for ischemic brain injury during the delayed phase.

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Human T-cell lymphotropic virus type 1 (HTLV-1) is a T lymphotropic human retrovirus that causes adult T-cell leukemia/lymphoma (ATL) and is associated with immunological disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A higher viral load in HTLV-1-infected individuals increases the risk of HAM/TSP and ATL; furthermore, it affects the disease severity of HAM/TSP. Therefore, the precise immune mechanisms controlling HTLV-1-infected cells must be further characterized. In this regard, the role of HTLV-1-specific CD8+ cytotoxic T lymphocytes (CTLs) has been studied intensively. However, there are few reports describing the role of innate immunity in controlling the proliferation of HTLV-1-infected cells. Natural killer (NK) and invariant natural killer T (iNKT) cells are the cellular components of innate immunity that regulate the immune response to general viral infection and cancers. Dendritic cells (DCs) play important roles in the activation of these NK and iNKT cells as well as CTLs. In this review, we summarize the characteristics of DCs, NK cells, and iNKT cells in individuals infected with HTLV-1. In the peripheral blood of HAM/TSP and ATL patients, the decreased number and impaired functionality of DCs, NK cells, and iNKT cells have been reported. Even in asymptomatic carriers, the functions of these cell populations are perturbed by HTLV-1 infection, while their frequencies are comparable to those of healthy individuals. These observations suggest that abnormalities of DCs, NK cells, and iNKT cells are implicated in the pathogenesis of HTLV-1-associated diseases via insufficient viral control.

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Mesenchymal stem cells (MSCs) are defined as cells that undergo sustained in vitro growth and are able of giving rise to multiple mesenchymal lineages. Although MSCs are already used in regenerative medicine, little is known about their in vivo behavior and developmental derivation. MSCs are a heterogeneous subset of stromal stem cells isolated from many adult tissues. Previous studies have reported that MSCs can differentiate into both mesodermal and neural lineages through a phenomenon referred to as “dedifferentiation” or “trans-differentiation”. Limb mesenchymal cells reportedly originate from the lateral plate mesoderm. An additional origin of MSCs is the neural crest. Here, we prospectively identified paraxial mesoderm-derived MSCs in the bone marrow of adult transgenic mice encoding early mesoderm-specific Mesp1-Cre/Floxed-EGFP. We observed that a small but significant amount of Mesp1⁺ cells existed in adult bone marrow. Interestingly, the detected EGFP⁺ cells in the bone marrow were mostly present in the haematopoietic cells and EGFP⁺ MSCs differentiated into osteocytes, adipocytes, chondrocytes, neurons, glial cells, and myofibroblasts. No significant differences in the in vitro characteristics were observed between EGFP⁺ and EGFP^- MSCs from Mesp1-Cre/Floxed-EGFP mice. Our results suggested that MSCs in adult bone marrow have a multi-developmental origin and that a portion of them are derived from Mesp1⁺ early paraxial mesoderm.

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