Ectopic PTH-producing parathyroid cyst inside the thymus: a case report.

BACKGROUND: The hallmark of hyperparathyroidism is hypersecretion of parathyroid hormone (PTH) which results in hypercalcemia and hypophosphatemia. While hypercalcemia due to malignancy is often brought about by PTH-related protein in adults, PTH-producing tumors are quite rare in clinical practice. Additionally, from the point of embryology, it is very difficult to examine ectopic PTH-producing tissue such as ectopic parathyroid glands. Furthermore, clear histopathological criteria are not present. CASE PRESENTATION: A 57-year-old woman was referred to our hospital for hypercalcemia. Her parathyroid hormone (PTH) level was elevated, but there were no enlarged parathyroid glands. Although 99mTc-MIBI confirmed a localized and slightly hyperfunctioning parathyroid tissue in the anterior mediastinum, it was not typical as hyperfunctioning parathyroid. We finally diagnosed her as ectopic PTH-producing cyst-like tumor with venous sampling of PTH. She underwent anterosuperior mediastinal ectopic PTH-producing cyst-like tumor resection. It is noted that intact-PTH concentration of the fluid in the cyst was very high (19,960,000 pg/mL). Based on histopathological findings, we finally diagnosed her as ectopic PTH-producing parathyroid cyst inside the thymus. After resection of anterosuperior mediastinal thymus including ectopic PTH-producing parathyroid cyst, calcium and intact-PTH levels were decreased, and this patient was discharged without any sequelae. CONCLUSIONS: We should know the possibility of superior mediastinal ectopic PTH-producing parathyroid cyst inside the thymus among subjects with ectopic PTH-producing parathyroid glands. Particularly when the cyst is present in the superior mediastinum, it is necessary to do careful diagnosis based on not only positive but also negative findings in 99mTc-MIBI. It is noted that the patient's bloody fluid in the cyst contained 19,960,000 pg/mL of intact-PTH, and its overflow into blood stream resulted in hyperparathyroidism and hypercalcemia. Moreover, in such cases, the diagnosis is usually confirmed after through histological examination of ectopic PTH-producing parathyroid glands. We think that it is very meaningful to let clinicians know this case.

Ectopic parathyroid hormone as a rare aetiology of hypercalcemia with rhabdomyosarcoma: a new treatment strategy with zoledronic acid and Denosumab.

OBJECTIVES: Ectopic parathyroid hormone (PTH) secretion is rare in children with rhabdomyosarcoma, and only a few pediatric cases have been reported to date. Reports of the use of zoledronic acid (ZA) and Denosumab are limited for the treatment of hypercalcemia of malignancy (HCM) in the pediatric population. The aim of presenting this pediatric case of rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH secretion, was to highlight the benefits of ZA as a first-choice bisphosphonate in this situation with Denosumab as an alternative therapy. CASE PRESENTATION: The patient was diagnosed at 13 years with alveolar rhabdomyosarcoma. Multiple bone metastases first appeared at 15 years, but he remained normocalcemic until 17 years old when serum calcium was 15.1 mg/dL and PTH 249 pg/mL. While serum calcium responded well after ZA and Denosumab cycles, PTH remained elevated, reaching a peak value of 1851 pg/mL during treatment cycles. CONCLUSIONS: We report a patient with rhabdomyosarcoma accompanied by HCM, secondary to ectopic PTH, in whom the HCM was successfully managed with ZA and Denosumab. We believe that ZA should be the bisphosphonate of choice in pediatric HCM with rhabdomyosarcoma, while Denosumab may be another option in ZA-refractory cases.

Role of resistin in cardiovascular diseases: Implications for prevention and treatment.

Cardiovascular diseases (CVDs) are associated with socioeconomic and, most importantly, with clinical problems. Accordingly, the identification of early and specific biomarkers indicating metabolic changes that underlie disease development and/or progression is important and may improve preventive and treatment strategies. A recently discovered protein - resistin (ADSF, FIZZ3) - whose expression is increased in carbohydrate metabolism and adipose tissue disorders, seems to be worth of interest in this context. The current publication was based on a detailed review of available literature, including Medline, EBSCO, Scopus, and Cochrane Library databases. The search period was between January 1, 2001 and December 20, 2020. The following keywords were used: "resistin", "resistin AND cardiology" and "resistin AND cardiosurgery". Our review covered a total of 4476 records, 594 of which were review publications. The presented article summarizes the current knowledge on the role of resistin in prevention and treatment of CVDs. Available literature shows that resistin may be a predictor for various pathological states; however, data from some studies on the pathophysiological mechanisms of action are contradictory. There is a need for further investigations to explore the exact role of resistin in CVDs.

Resistin-like molecule ß acts as a mitogenic factor in hypoxic pulmonary hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK signaling pathways.

BACKGROUND: Pulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule ß (RELM-ß) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-ß has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-ß in HPH remain unclear. METHODS: We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-ß in a rat HPH model and in hPASMCs. RESULTS: Overexpression of RELM-ß caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-ß partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-ß gene overexpression or silencing, respectively. Recombinant RELM-ß protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-ß on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor. CONCLUSIONS: Our findings suggest that RELM-ß acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-ß are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Surgical correction of bilateral ectopic ureter using the neoureterocystostomy technique / Correção cirúrgica de ureter ectópico bilateral utilizando a técnica de neoureterocistostomia

Ureteral ectopy is a rare disorder in the small animals' clinic. It is characterized as a congenital anomaly, resulting from the ducts differentiation failure during embryogenesis. In this scenario, the ureters present themselves outside the anatomical site, being inserted into the uterus, urethra, urinary vesicle neck, or vagina. The clinical signs are urinary incontinence and perivulvar dermatitis. Surgery is the accepted treatment to correct the anomaly. The surgical procedure is based on relocating the ectopic ureter and treating associated modifications. This report describes a case of intramural bilateral ureteral ectopy, corrected surgically through the neoureterocystostomy technique, making it possible to control the animal's urinary incontinence.(AU)

A ectopia ureteral é uma afecção de incidência rara na clínica de pequenos animais, sendo caracterizada como anomalia congênita resultante de falha na diferenciação dos ductos durante a embriogênese. Neste cenário, os ureteres se apresentam fora do seu local anatômico, sendo inseridos no útero, no colo da vesícula urinária, na uretra ou na vagina. Os sinais clínicos comumente apresentados são a incontinência urinária bem como a dermatite perivulvar. O tratamento de eleição para correção da anomalia é o procedimento cirúrgico, no qual a técnica de escolha é baseada na relocação do ureter ectópico e tratamento das alterações associadas. Neste contexto, o presente relato descreve um caso de ectopia ureteral bilateral intramural, corrigido cirurgicamente por meio da técnica neoureterocistostomia, o que possibilitou controle da incontinência urinária do paciente.(AU)

[CME: Paraneoplastic Endocrine Syndromes]. / CME: Paraneoplastische endokrine Syndrome.

CME: Paraneoplastic Endocrine Syndromes Abstract. Paraneoplastic endocrine syndromes are caused by ectopic hormone production by malignant tumor cells. Knowledge of paraneoplastic endocrine syndromes may allow a timely diagnosis of the underlying cancer at a treatable stage and, on the other hand, appropriate treatment of the endocrine manifestations reduces morbidity and mortality of the affected patients. The most common endocrine syndromes are paraneoplastic hypercalcaemia, caused by the secretion of PTHrP, and hyponatremia, caused by the inadequate secretion of ADH. Although there may be clinical symptoms like fatigue, nausea/vomiting and renal insufficiency for hypercalcaemia and gait disturbances and mental alterations for hyponatremia, the diagnosis must be confirmed by laboratory testing and prompt the search for associated tumors.

Lactobacillus salivarius reverse antibiotic-induced lung defense impairment in a ventilator model.

BACKGROUND: Widespread use of antibiotics in the intensive care unit is a potential cause of the emergence of hospital-acquired pneumonia. This study determined whether Lactobacillus salivarius feeding could reverse antibiotic-induced lung defense impairment in a ventilator model. METHODS: C57BL/6 wild-type (WT) mice received mechanical ventilation for 3 h after intramuscular antibiotic treatment for 6 days. Treatment with dead Lactobacillus salivarius and fructo-oligosaccharides (FOS) feeding were used to stimulate antibacterial protein expression in the intestine. Reactive oxygen species (ROS) in the intestinal mucosa was detected using 2'7'-dichlorofluorescein diacetate. The peroxynitrite production of alveolar macrophages (AMs) was measured using dihydrorhodamine 123 oxidation assay. N-acetylcysteine (NAC), an ROS scavenger, was orally administered to mice receiving antibiotics with FOS feeding. RESULTS: Antibiotic treatment decreased Pseudomonas aeruginosa (PA) phagocytic activity and activity of AMs and protein expression of regenerating islet-derived protein 3ß (Reg3ß) as well as Toll-like receptor 4 (TLR4) in the intestinal mucosa in the ventilator model. Antibiotic treatment also decreased ROS production in the intestinal mucosa, peroxynitrite production of AMs, and RELMß expression as well as NF-κB DNA binding activity of the intestinal mucosa in WT mice but not in MyD88-/- mice. Treatment with dead L. salivarius or FOS feeding increased ROS production, bacterial killing activity, and protein expression of Reg3ß as well as TLR4 in the intestinal mucosa and reversed the inhibitory effects of antibiotics on PA phagocytic activity of AMs. CONCLUSION: Taken together with the finding that ablation of FOS-induced intestinal ROS using NAC decreased peroxynitrite production as well as PA phagocytic activity of AMs and protein expression of CRP-ductin, IL-17, Reg3ß, and RELMß in the intestinal mucosa, we conclude that commensal microflora plays a key role in stimulating lung immunity. Intestinal ROS plays a role as a predictive indicator and modulator of pulmonary defense mechanisms. Antibiotic treatment reduces lung defense against PA infection through the decrease in intestinal Reg3ß and TLR4 expression. Treatment with dead L. salivarius or FOS feeding reverses the antibiotic-induced lung defense impairment through the intestinal ROS/MyD88 pathways.

Chronic features of allergic asthma are enhanced in the absence of resistin-like molecule-beta.

Asthma is characterized by inflammation and architectural changes in the lungs. A number of immune cells and mediators are recognized as initiators of asthma, although therapeutics based on these are not always effective. The multifaceted nature of this syndrome necessitate continued exploration of immunomodulators that may play a role in pathogenesis. We investigated the role of resistin-like molecule-beta (RELM-ß), a gut antibacterial, in the development and pathogenesis of Aspergillus-induced allergic airways disease. Age and gender matched C57BL/6J and Retnlb-/- mice rendered allergic to Aspergillus fumigatus were used to measure canonical markers of allergic asthma at early and late time points. Inflammatory cells in airways were similar, although Retnlb-/- mice had reduced tissue inflammation. The absence of RELM-ß elevated serum IgA and pro-inflammatory cytokines in the lungs at homeostasis. Markers of chronic disease including goblet cell numbers, Muc genes, airway wall remodelling, and hyperresponsiveness were greater in the absence RELM-ß. Specific inflammatory mediators important in antimicrobial defence in allergic asthma were also increased in the absence of RELM-ß. These data suggest that while characteristics of allergic asthma develop in the absence of RELM-ß, that RELM-ß may reduce the development of chronic markers of allergic airways disease.

[Endocrine paraneoplastic syndromes]. / Endokrine paraneoplastische Syndrome.

Endocrine paraneoplastic syndromes result from the production of bioactive substances from neoplastic cells, of endocrine or neuroendocrine origin. Typically these are located in the lungs, the gastrointestinal tract, pancreas, thyroid gland, adrenal medulla, skin, prostate or breast. In endocrine paraneoplastic syndromes the secretion of peptides, amines or other bioactive substances is always ectopic and not related to the anatomical source. The clinical presentation, however, is indistinguishable from a suspected eutopic endocrine tumor posing a diagnostic challenge. The most common endocrine paraneoplastic syndromes are based on the secretion of antidiuretic hormone (ADH) resulting in hyponatremia, secretion of adrenocorticotropic hormone (ACTH) or rarely corticotropin-releasing hormone (CRH) resulting in Cushing syndrome as well as secretion of growth hormone-releasing hormone resulting in acromegaly. Paraneoplastic endocrine syndromes mainly occur in highly malignant tumors; however, the development of these tumors does not necessarily correlate with tumor stage, malignant potential or prognosis. As endocrine paraneoplastic syndromes are a rare complication, there are hardly any evidence-based therapeutic recommendations. Treatment of the underlying tumor is the first choice and in a palliative setting symptomatic therapy is possible.

Resistin-like molecule ß is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium.

The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule ß (RELMß) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMß selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMß, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMß promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.

Hiperglucemia como manifestación infrecuente de carcinoma microcítico de pulmón con secreción ectópica de hormona adrenocorticotropa / Hyperglycaemia as an unusual manifestation of small cell lung carcinoma with ectopic adrenocorticotropic hormone secretion

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Localization of RELM-ß/FIZZ2 Is Associated with Cementum Formation.

Resistin-like molecule-ß/found in inflammatory zone 2 (RELM-ß/FIZZ2) is a cysteine-rich secretory protein that is localized in the epithelium of the gastrointestinal tract and lung alveoli. Previous reports have suggested that this protein regulates glucose metabolism and inflammation. In the present study, to analyze the involvement of RELM-ß/FIZZ2 in tooth development, we immunohistochemically examined the localization of RELM-ß/FIZZ2 in tooth germs of embryonic days (E) 15-20 and postnatal days (P) 7-42 rats. RELM-ß/FIZZ2 was hardly detected in the tooth germ at the bud (E15) stage. However, at the cap (E17) and bell (E20) stages, this protein was detectable in the inner enamel epithelium; whereas cells in the other parts of the enamel organ including the outer enamel epithelium and stellate reticulum did not show the immunoreactivity. During the root formation stage (P14-28), cells in Hertwig's epithelial root sheath (HERS) localized RELM-ß/FIZZ2. Intense immunoreactivity was also seen in the matrix of the root dentin facing the HERS and the dental follicle. This reactivity was not present on the more upwardly located dentin surface. In contrast, cementum matrix positive for osteopontin and bone sialoprotein was observed on the dentin instead of immunoreactivity for RELM-ß/FIZZ2. Osterix-positive cells, indicating cementoblast progenitors, were also detected in the dental follicle near the matrix positive for RELM-ß/FIZZ2. These results suggest that RELM-ß/FIZZ2 secreted by the inner enamel epithelium was mainly localized in the matrix at the surface of the apical root dentin and might be involved in cementogenesis. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1865-1874, 2017. © 2017 Wiley Periodicals, Inc.

Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity.

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

Metabolic In Vivo Visualization of Pituitary Adenomas: a Systematic Review of Imaging Modalities.

OBJECTIVE: Pituitary adenomas (PAs) are the most common intrasellar mass. Functional PAs constitute most of pituitary tumors and can produce symptoms related to hormonal overproduction. Timely and accurate detection is therefore of vital importance to prevent potentially irreversible sequelae. Magnetic resonance imaging is the gold standard for detecting PAs, but is limited by poor sensitivity for microadenomas and an inability to differentiate scar tissue from tumor residual or predict treatment response. Several new modalities that detect PAs have been proposed. METHODS: A systematic review of the PubMed database was performed for imaging studies of PAs since its inception. Data concerning study characteristics, clinical symptoms, imaging modalities, and diagnostic accuracy were collected. RESULTS: After applying exclusion criteria, 25 studies of imaging PAs using positron emission tomography (PET), magnetic resonance spectroscopy (MRS), and single photon emission computed tomography were reviewed. PET reliably detects PAs, particularly where magnetic resonance imaging is equivocal, although its efficacy is limited by high cost and low availability. Single photon emission computed tomography possesses good sensitivity for neuroendocrine tumors but its use with PAs is poorly documented. MRS consistently detects cellular proliferation and hormonal activity, but warrants further study at higher magnetic field strength. CONCLUSIONS: PET and MRS appear to have the strongest predictive value in detecting PAs. MRS has the advantage of low cost, but the literature is lacking in specific studies of the pituitary. Due to high recurrence rates of functional PAs and low sensitivity of existing diagnostic workups, further investigation of metabolic imaging is necessary.

Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma.

A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental glomerulosclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma.

Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri.

Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri Genetic deletion of IL-25 (IL-25-/-) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25-/- mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25-/- mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.

Lactobacillus salivarius reverse diabetes-induced intestinal defense impairment in mice through non-defensin protein.

Altered intestinal microbiota and subsequent endotoxemia play pathogenic roles in diabetes. We aimed to study the mechanisms of intestinal defense impairment in type 1 diabetes and the effects of Lactobacillus salivarius as well as fructooligosaccharides (FOS) supplementation on diabetes-induced bacterial translocation. Alterations in the enteric microbiome, expression of mucosal antibacterial proteins and bacteria-killing activity of the intestinal mucosa in streptozotocin (STZ)-induced diabetic mice and Ins2(Akita) mice were investigated. The effects of dead L. salivarius (2×10(8)CFU/ml) and FOS (250 mg per day) supplementation for 1 week on endotoxin levels and Klebsiella pneumoniae translocation were also examined. Finally, germ-free mice were cohoused with wild-type or Ins2(Akita) mice for 2 weeks to examine the contribution of microbiota on the antibacterial protein expression. STZ-induced diabetic mice developed intestinal defense impairment as demonstrated by decreased mucosal bacteria-killing activity; reduction of non-defensin family proteins, such as Reg3ß, Reg3γ, CRP-ductin and RELMß, but not the defensin family proteins; and increased bacterial translocation. Intestinal bacteria overgrowth, enteric dysbiosis and increased intestinal bacterial translocation, particularly pathogenic K. pneumoniae in STZ-induced diabetic mice and Ins2(Akita) mice, were noted. Treating diabetic mice with dead L. salivarius or FOS reversed enteric dysbiosis, restored mucosal antibacterial protein and lessened endotoxin levels as well as K. pneumoniae translocation. Moreover, germ-free mice cohoused with wild-type mice demonstrated more intestinal Reg3ß and RELMß expression than those cohoused with Ins2(Akita) mice. These results indicate that hyperglycemia induces enteric dysbiosis, reduction of non-defensin proteins as well as bacteria-killing activity of the intestinal mucosa and intestinal defense impairment. Reversal of enteric dysbiosis with dead L. salivarius or FOS supplementation decreases diabetes-induced K. pneumoniae translocation and endotoxin levels through the induction of non-defensin proteins.

Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlß (RELMß) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility.

Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMß, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMß has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMß plays a complex role in immune system regulation, and the impact of loss of function of RELMß on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlß (mouse ortholog of human RETNLß) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMß leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlß null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype.

Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

Comparison of RELMα and RELMß Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection.

Resistin-like molecules (RELMs) are highly expressed following helminth infection, where they impact both the host and helminth. While RELMα (Retnla) impairs helminth expulsion by inhibiting protective Th2 immunity, RELMß (Retnlb) can promote its expulsion. We employed Retnla(-/-) and Retnlb(-/-) mice to delineate the function of both proteins following infection with Nippostrongylus brasiliensis, a hookworm that infects the lung and intestine. Whereas wild-type (WT) and Retnlb(-/-)mice exhibited equivalent infection-induced inflammation, Retnla(-/-) mice suffered a heightened inflammatory response, including increased mortality, weight loss, and lung inflammation. In the intestine, Retnla(-/-)mice had low parasite egg burdens compared to those of WT mice, while Retnlb(-/-) mice exhibited high egg burdens, suggesting that RELMα and RELMß have functionally distinct effects on immunity and inflammation to N. brasiliensis To test the importance of both proteins, we generated Retnla(-/-) Retnlb(-/-) mice. Infected Retnla(-/-)Retnlb(-/-) mice exhibited similar responses to Retnla(-/-) mice, including increased mortality and lung inflammation. This inflammatory response in Retnla(-/-) Retnlb(-/-) mice negatively impacted N. brasiliensis fitness, as demonstrated by significantly lower worm ATP levels and decreased intestinal worm burden and fecundity. Lung cytokine analysis revealed that Retnla(-/-) and Retnla(-/-) Retnlb(-/-) mice expressed significantly increased levels of interleukin-4 (IL-4). Finally, we generated Retnla(-/-) mice on the Rag(-/-) background and observed that the effects of RELMα were abrogated in the absence of adaptive immunity. Together, these data demonstrate that RELMα but not RELMß significantly impacts the immune response toN. brasiliensis infection by downregulating the Th2 adaptive immune response in the lung, which protects the host but allows improved parasite fitness.