Cytokines and NLRC4-Dysregulated Diseases

The NLRC4 inflammasome assembles in response to detection of bacterial invasion, and NLRC4 activation leads to the production of IL-1β and IL-18 together with pyroptosis-mediated cell death. Missense activating mutations in NLRC4 cause autoinflammatory disorders whose symptoms are distinctly dependent on the site of mutation and other aspects of the genetic background. To determine the involvement of IL-1β and IL-18 in the inflammation induced by NLRC4 mutation, we depleted IL-1β, IL-18, or both cytokines in Nlrc4-transgenic mice in which mutant Nlrc4 is expressed under the MHC class II promoter (Nlrc4-H443P-Tg mice). The deletion of the Il1b or Il18 gene in Nlrc4-H443P-Tg mice reduced the neutrophil numbers in the spleen, and mice with deletion of both genes had an equivalent number of neutrophils compared to wild-type mice. Deletion of Il1b ameliorated but did not eliminate bone marrow hyperplasia, while mice deficient in Il18 showed no bone marrow hyperplasia. In contrast, tail bone deformity remained in the presence of Il18 deficiency, but Il1b deficiency completely abolished bone deformity. The decreased bone density in Nlrc4-H443P-Tg mice was counteracted by Il1b but not Il18 deficiency. Our results demonstrate the distinct effects of IL-1β and IL-18 on NLRC4-induced inflammation among tissues, which suggests that blockers for each cytokine should be utilized depending on the site of inflammation

Inverted ductal papilloma arising from the buccal minor salivary gland: A case report and immunohistochemical study

AbstractOral inverted ductal papilloma is a rare, benign epithelial tumor that exhibits an endophytic growth pattern and is found almost exclusively in the minor salivary glands. We report on a case of inverted ductal papilloma in the buccal mucosa. We also performed an immunohistochemical study. The tumor cells were positive for cytokeratin and epithelial membrane antigen, while negative for calponin, S-100 protein, α-SMA, vimentin, and desmin. This result indicated that the lesion arises from the excretory duct near the oral mucosal surface but not the myoepithelial cells. In addition, Ki-67 labeling index of 3.96% indicated the low level of proliferation

Blockade of the CXCR3/CXCL10 axis ameliorates inflammation caused by immunoproteasome dysfunction

Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and generate peptides that are preferentially presented by MHC class I. Mutations in immunoproteasome subunits lead to immunoproteasome dysfunction, which causes proteasome-associated autoinflammatory syndromes (PRAAS) characterized by nodular erythema and partial lipodystrophy. It remains unclear, however, how immunoproteasome dysfunction leads to inflammatory symptoms. Here, we established mice harboring a mutation in Psmb8 (Psmb8-KI mice) and addressed this question. Psmb8-KI mice showed higher susceptibility to imiquimod-induced skin inflammation (IMS). Blockade of IL-6 or TNF-α partially suppressed IMS in both control and Psmb8-KI mice, but there was still more residual inflammation in the Psmb8-KI mice than in the control mice. DNA microarray analysis showed that treatment of J774 cells with proteasome inhibitors increased the expression of the Cxcl9 and Cxcl10 genes. Deficiency in Cxcr3, the gene encoding the receptor of CXCL9 and CXCL10, in control mice did not change IMS susceptibility, while deficiency in Cxcr3 in Psmb8-KI mice ameliorated IMS. Taken together, these findings demonstrate that this mutation in Psmb8 leads to hyperactivation of the CXCR3 pathway, which is responsible for the increased susceptibility of Psmb8-KI mice to IMS. These data suggest the CXCR3/CXCL10 axis as a new molecular target for treating PRAAS

Differentiation of preadipocytes and mature adipocytes requires PSMB8

The differentiation of adipocytes is tightly regulated by a variety of intrinsic molecules and also by extrinsic molecules produced by adjacent cells. Dysfunction of adipocyte differentiation causes lipodystrophy, which impairs glucose and lipid homeostasis. Although dysfunction of immunoproteasomes causes partial lipodystrophy, the detailed molecular mechanisms remain to be determined. Here, we demonstrate that Psmb8, a catalytic subunit for immunoproteasomes, directly regulates the differentiation of preadipocytes and additionally the differentiation of preadipocytes to mature adipocytes. Psmb8−/− mice exhibited slower weight gain than wild-type mice, and this was accompanied by reduced adipose tissue volume and smaller size of mature adipocytes compared with controls. Blockade of Psmb8 activity in 3T3-L1 cells disturbed the differentiation to mature adipocytes. Psmb8−/− mice had fewer preadipocyte precursors, fewer preadipocytes and a reduced ability to differentiate preadipocytes toward mature adipocytes. Our data demonstrate that Psmb8-mediated immunoproteasome activity is a direct regulator of the differentiation of preadipocytes and their ultimate maturation

Dysfunctional immunoproteasomes in autoinflammatory diseases

Recent progress in DNA sequencing technology has made it possible to identify specific genetic mutations in familial disorders. For example, autoinflammatory syndromes are caused by mutations in gene coding for immunoproteasomes. These diseases include Japanese autoinflammatory syndrome with lipodystrophy, Nakajo-Nishimura syndrome, joint contractures, muscular atrophy, microcytic anemia, panniculitis-associated lipodystrophy syndrome, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. Causal mutations of these syndromes are present in gene coding for subunits of the immunoproteasome. Importantly, a genetically modified mouse that lacks the catalytic subunit of immunoproteasomes does not always develop an autoinflammatory syndrome. Analysis of causal gene mutations, assessment of patients’ phenotypic changes, and appropriate animal models will be indispensable for clarifying the underlying mechanisms responsible for the development of autoinflammatory syndromes and establishing curative approaches

Diagnostic Ureteroscopy for Cases Clinically Suspected of Carcinoma in Situ of the Upper Urinary Tract

　We elucidate the fate of cases clinically suspected of carcinoma in situ (Cis) of the upper tract with serial ureteroscopy. Of 143 patients who underwent ureteroscopy for suspected upper tract urothelial carcinoma (UTUC) between January 2008 and February 2016, 12 cases with consistently positive urine cytology and poorly detectable upper-tract malignancies by imaging were reviewed. In these 12 patients, 19 ureteroscopy procedures (25 renal units) were performed. Vesical random biopsy was performed before the 1st ureteroscopy to exclude malignancy of the bladder in all 12 cases. Median follow-up was 42 (13-67) months. Positive biopsy results at the 1st ureteroscopy were obtained in 3 (25%) patients and all were diagnosed wth Cis of the upper tract. Two (17%) of 9 patients who were negative or inconclusive at the 1st ureteroscopy were finally diagnosed as UTUC, but plural ureteroscopy procedures were needed for the diagnoses in both. Carcinoma of the bladder appeared in 5 (42%) patients during follow-up, despite the earlier ruling out of vesical malignancy. Four (33%) of those 5 patients never developed upper-tract urothelial carcinoma during follow-up. Caution is required before undertaking radical surgery for cases clinically suspected of Cis of the upper tract. In our experience, only 42% of such patients developed UTUC; another 33% eventually developed carcinoma of the bladder without UTUC

Factors Predicting Adhesion between Renal Capsule and Perinephric Adipose Tissue in Partial Nephrectomy

In minimally invasive partial nephrectomy (MIPN), it is important to preoperatively predict the degree of difficulty of tumor resection. When severe adhesions occur between the renal capsule and perinephric adipose tissue, detachment can be difficult. Preoperative prediction of adhesion is thought to be useful in the selection of surgical procedure. Subjects were 63 patients of a single surgeon who had received MIPN between April 2008 and August 2013 at Okayama University Hospital. Of these patients, this study followed 47 in whom the presence or absence of adhesions between the renal capsule and perinephric adipose tissue was confirmed using intraoperative videos. Data collected included: sex, BMI, CT finding (presence of fibroids in perinephric adipose tissue), comorbidities and lifestyle. Adhesion was observed in 7 patients (14.9%). The mean operative time was 291.6min in the adhesion group, and 226.3min in the group without. The increased time in the adhesions group was significant (p＜0.05). Predictive factors were a positive CT finding for fibroid structure and comorbidity of hypertension (p＜0.05). In MIPN, difficulty of surgery can be affected by the presence of adhesion of the perinephric adipose tissue. Predicting such adhesion from preoperative CT is thus important

Ureteroscopic Management of Chronic Unilateral Hematuria: A Single-Center Experience over 22 Years

OBJECTIVE: To analyze the short and long term safety and efficacy of ureteroscopic evaluation and management of chronic unilateral hematuria. METHODS: We retrospectively reviewed patients with chronic unilateral hematuria from 1987 to 2008. The distal to middle ureter was evaluated with a semi-rigid ureteroscope without a guidewire. Subsequently, the flexible ureteroscope was advanced into the upper ureter to the renal pelvis using a low-pressure automated irrigant system (Uromat™). Lesions identified ureteroscopically were treated with diathermy fulguration. RESULTS: One hundred and four (56 male, 48 female) patients were identified, with a median age of 37 (14-80) years and median follow-up of 139 (34-277) months. The median preoperative duration of gross hematuria was 5 (1-144) months. Endoscopic findings included 61 (56%) minute venous rupture (MVR; a venous bleeding without clear abnormalities), 21 (20%) hemangioma (vascular tumor-like structure), 3 (3%) varix (tortuous vein), 1 (1%) calculus and 18 (17%) no lesions. The incidence of "no lesions" was less in the recent 12 years (9%) than the first 10 years (27%), while the incidence of MVR increased from 40 to 66% (p<0.05). All patients were treated endoscopically. Immediate success rate was 96% (100% in the recent 12 years). Long-term recurrent gross hematuria rate was 7%. Six resolved spontaneously and only 1 required ureteroscopy, revealing a different bleeding site. CONCLUSION: Ureteroscopy and diathermy fulguration is highly useful for evaluation and treatment of chronic unilateral hematuria. Sophisticated technique and improved instrumentation contributes to a better outcome

Stimulation of the farnesoid X receptor promotes M2 macrophage polarization

FXR is a key molecule that modulates anti-inflammatory activity in the intestinal-liver axis. Although FXR has pleiotropic functions including regulation of liver inflammation and activation of macrophages, it remains unclear whether it is involved in macrophage polarization. In this paper we demonstrated that stimulation of macrophages derived from the bone marrow using an FXR agonist activated polarization toward M2 but not M1 macrophages. The treatment of mice with chitin skewed macrophage polarization towards M2 macrophages, while co-treatment with an FXR agonist further promoted the polarization toward M2 macrophages in vivo. This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions