Browsing by Subject "inflammation"
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Item Open Access An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger.(International journal of molecular sciences, 2022-11) Berger, Shane N; Baumberger, Beatrice; Samaranayake, Srimal; Hersey, Melinda; Mena, Sergio; Bain, Ian; Duncan, William; Reed, Michael C; Nijhout, H Frederik; Best, Janet; Hashemi, ParastooHistamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine's neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools. We find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptors and metabolism. We find two breakthrough aspects of histamine modulation. First, differences in H3 receptor regulation between sexes show that histamine release in female mice is much more tightly regulated than in male mice under H3 or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, a high dose of a commonly available antihistamine, the H1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This finding highlights the sheer significance of pharmaceuticals on neuromodulation. Our study opens the path to better understanding and treating histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics.Item Open Access Blocking CCL8-CCR8-Mediated Early Allograft Inflammation Improves Kidney Transplant Function.(Journal of the American Society of Nephrology : JASN, 2022-08-16) Dangi, Anil; Husain, Irma; Jordan, Collin Z; Yu, Shuangjin; Natesh, Naveen; Shen, Xiling; Kwun, Jean; Luo, Xunrong; Luo, XunrongBackground
In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions.Methods
We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients.Results
Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function.Conclusions
Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.Item Open Access Calcium Pyrophosphate And Monosodium Urate Activate The NLRP3 Inflammasome Within Bladder Urothelium Via Reactive Oxygen Species And TXNIP.(Research and reports in urology, 2019-01) Harper, Shelby N; Leidig, Patrick D; Hughes, Francis M; Jin, Huixia; Purves, J ToddObjective:To investigate the in vitro activation of the NLRP3 inflammasome within bladder urothelium by stone-forming components. Further, to describe the contributions of reactive oxygen species (ROS) and thioredoxin-interacting protein (TXNIP), an important structural component of the inflammasome, to this activation. Methods:Urothelial cells were harvested and incubated overnight. For agonist studies, cells were treated with varying concentrations of calcium pyrophosphate (CPPD) and monosodium urate (MSU). For inhibitor studies, cells were treated with either N-acetylcysteine (NAC) (1 hr) or Verapamil (4 hrs) prior to incubation with either CPPD (62.5 ug/mL) or MSU (1.25 ug/mL) for 24 hrs. Untreated controls were incubated with ATP (1.25 mM) for 1 hr to maximally stimulate NLRP3 inflammasome activity (measured as caspase-1 cleavage of the fluorogenic substrate Ac-YVAD-AFC). Results are reported as a percentage of maximum ATP response. Results:CPPD and MSU activate caspase-1 in urothelial cells in a dose-dependent manner, reaching ~50% and ~25% of the ATP response, respectively. Pre-treatment with the general ROS scavenger NAC reduces this activation in a dose-dependent manner. Additionally, activation was suppressed through treatment with Verapamil, a known downregulator of TXNIP expression. Conclusion:The stone components CPPD and MSU activate NLRP3 in an ROS and TXNIP-dependent manner in bladder urothelium. These findings demonstrate the importance of ROS and TXNIP, and suggest that targeting either may be a way to decrease stone-dependent NLRP3 inflammation within the bladder.Item Open Access Combined Inflammation and Metabolism Biomarker Indices of Robust and Impaired Physical Function in Older Adults.(Journal of the American Geriatrics Society, 2018-05-08) Zuo, Xintong; Luciano, Alison; Pieper, Carl F; Bain, James R; Kraus, Virginia B; Kraus, William E; Morey, Miriam C; Cohen, Harvey JTo determine whether combinations of inflammatory markers are related to physical function.secondary analysis of baseline of three observational studies of community-dwelling older adults MEASUREMENTS: The baseline data from 3 cohorts of older adults with different health and disease status were employed. Twenty markers of inflammation and metabolism were individually assessed for correlation with usual gait speed and were separated into robust and impairment quartiles. For the robustness and impairment indices, individual markers were selected using step-wise regression over bootstrapping iterations, and regression coefficients were estimated for the markers individually and collectively as an additive score.We developed a robustness index involving 6 markers and an impairment index involving 8 markers corresponding positively and negatively with gait speed. Two markers, glycine and tumor necrosis factor receptor 1 (TNFR1), appeared only in the robustness index, and TNFR2; regulated on activation, normal T-cell expressed and secreted; the amino acid factor; and matrix metallopeptidase 3; appeared only in the impairment index.Indices of biomarkers were associated with robust and impaired physical performance but differ, in composition suggesting potential biological differences that may contribute to robustness and impairment.Item Open Access Country of residence is associated with distinct inflammatory biomarker signatures in HIV-infected patients.(J Virus Erad, 2017-01-01) Manion, Maura; Andrade, Bruno B; DerSimonian, Rebecca; Gu, Wenjuan; Rupert, Adam; Musselwhite, Laura W; Sierra-Madero, Juan G; Belaunzaran-Zamudio, Pablo F; Sanne, Ian; Lederman, Michael M; Sereti, IriniBACKGROUND: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection. METHODS: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts <100 cells/μl from Mexico (n=124) and South Africa (n=143). Biomarkers were compared and dimension reduction analyses were performed to highlight biosignatures according to nationality, gender and tuberculosis co-infection. RESULTS: Mexican patients were significantly different from South Africans with regard to age, gender, CD4 cell count, haemoglobin, presence of AIDS-defining illness and prevalence of active tuberculosis. After adjusting for baseline characteristics, patients from Mexico had higher levels of IFN-γ, IL-8, and CXCL-10 whereas patients from South Africa had higher levels of fibrinogen, LTB4, P-selectin, protein S, and sCD40 ligand. The effect of country on the profile of biomarker expression was stronger than gender differences and tuberculosis co-infection. CONCLUSION: Inflammation and coagulation biomarkers vary significantly by country. Further studies are needed to evaluate how these differences may contribute to HIV pathogenesis and prognosis in diverse populations and how they can be accounted for in studies using biomarkers as surrogate end points.Item Open Access CXCL10 is Upregulated in Synovium and Cartilage following Articular Fracture.(J Orthop Res, 2017-09-14) Furman, Bridgette D; Kent, Collin L; Huebner, Janet L; Kraus, Virginia B; McNulty, Amy L; Guilak, Farshid; Olson, Steven AThe objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) vs. three days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p=0.09) and S-GAG (p=0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. This article is protected by copyright. All rights reserved.Item Open Access Diabetic bladder dysfunction is associated with bladder inflammation triggered through hyperglycemia, not polyuria(Research and Reports in Urology, 2018-11-16) Inouye, BM; Hughes, FM Jr; Jin, H; Lütolf, R; Potnis, KC; Routh, JC; Rouse, dc; Foo, WC; Purves, JTPurpose
Diabetes is a grave and progressive condition characterized by debilitating complications. Diabetic bladder dysfunction (DBD) is a very common complication with no specific treatments currently available. Unlike other tissues affected by this disease, the bladder is subjected to two independent insults; 1) polyuria, created by the osmotic effects of glucose in the urine, and 2) hyperglycemia itself. Based on our understanding of inflammation as a major contributor to the underlying organ damage in several other diabetic complications, its presence in the bladder during DBD and the contribution of polyuria and hyperglycemia to its development were assessed.Methods
Awake, restrained cystometry was performed on wild type C57BL/6 mice and diabetic (Akita) mice on a C57BL/6 background at 15 weeks of age. A subgroup of the Akita mice were treated with phlorizin, an inhibitor of sodium-glucose linked transporter types 1 and 2 that prevents glucose reabsorption in the kidney. All groups were assessed for serum glucose, 4-hour voiding totals, and inflammation in the bladder (Evans blue assay).Results
Akita mice develop cystometrically-defined DBD by 15 weeks of age, as evidenced by an increase in urinary frequency, a decrease in voiding volume, and an increase in post-voiding residual volume. Phlorizin effectively normalized serum glucose in these animals while increasing the urine output. Inflammation in the bladder was present in the diabetic animals at this time point, but not detectable in animals receiving phlorizin.Conclusion
Inflammation in the bladder of diabetic mice correlates with the development of DBD and is triggered by hyperglycemia, not polyuria.Item Open Access Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.(Cancers, 2022-05) Zhu, Liang; Ji, Juntao; Ma, Jianjia; Wang, Dan; Liu, Muyun; Du, James Xianxing; Chen, Rong; Hou, Wei; Abbruzzese, James L; Logsdon, Craig D; Yang, Vincent W; Luo, Yongde; Lu, WeiqinKRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.Item Open Access Genetic Abrogation of Adenosine A3 Receptor Prevents Uninephrectomy and High Salt-Induced Hypertension.(J Am Heart Assoc, 2016-07-18) Yang, Ting; Zollbrecht, Christa; Winerdal, Malin E; Zhuge, Zhengbing; Zhang, Xing-Mei; Terrando, Niccolo; Checa, Antonio; Sällström, Johan; Wheelock, Craig E; Winqvist, Ola; Harris, Robert A; Larsson, Erik; Persson, A Erik G; Fredholm, Bertil B; Carlström, MattiasBACKGROUND: Early-life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A3 receptor in cardiovascular diseases is not clear. In this study, gene-modified mice were used to investigate the hypothesis that lack of A3 signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX-HS) in mice. METHODS AND RESULTS: Wild-type (A3 (+/+)) mice subjected to UNX-HS developed hypertension compared with controls (mean arterial pressure 106±3 versus 82±3 mm Hg; P<0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A3 (-/-) mice. Mechanistically, absence of A3 receptors protected from UNX-HS-associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1β, 6, 12, and 10 were increased in A3 (+/+) following UNX-HS, but these cytokines were already elevated in naïve A3 (-/-) mice and did not change following UNX-HS. CONCLUSIONS: Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A3 receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.Item Open Access Histological and Inflammatory Cytokine Analysis of Osteochondral Lesions of the Talus After Failed Microfracture: Comparison With Fresh Allograft Controls.(Orthopaedic journal of sports medicine, 2021-10-29) Danilkowicz, Richard M; Allen, Nicholas B; Grimm, Nate; Nettles, Dana L; Nunley, James A; Easley, Mark E; Adams, Samuel BBackground
The most common first-line treatment of osteochondral lesions of the talus (OLTs) is microfracture. Although many patients do well with this procedure, a number fail and require reoperation. The mechanism of failure of microfracture is unknown, and to our knowledge there has been no research characterizing failed microfracture regarding histological and inflammatory makeup of these lesions that may contribute to failure.Purpose
To characterize the structural and biochemical makeup of failed microfracture lesions.Study design
Case series; Level of evidence, 4.Methods
Specimens from 8 consecutive patients with symptomatic OLTs after microfracture who later underwent fresh osteochondral allograft transplantation were analyzed. For each patient, the failed microfracture specimen and a portion of the fresh allograft replacement tissue were collected. The allograft served as a control. Histology of the failed microfracture and the allograft replacement was scored using the Osteoarthritis Research Society International (OARSI) system. Surface roughness was also compared. In addition, tissue culture supernatants were analyzed for 16 secreted cytokines and matrix metalloproteinases (MMPs) responsible for inflammation, pain, cartilage damage, and chondrocyte death.Results
The OARSI grade, stage, and total score as well as surface smoothness were significantly worse in the failed microfracture sample, indicating better cartilage and bone morphology for the allografts compared with the failed microfracture lesions. Analyzed cytokines and MMPs were significantly elevated in the microfracture tissue culture supernatants when compared with fresh osteochondral tissue supernatants.Conclusion
These data demonstrate a significantly rougher cartilage surface, cartilage and subchondral bone histology that more closely resembles osteoarthritis, and elevated inflammatory cytokines and MMPs responsible for pain, inflammation, cartilage damage, and chondrocyte death when compared with fresh osteochondral allografts used as controls.Item Open Access Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity.(Journal of asthma and allergy, 2021-01) Womble, Jack T; McQuade, Victoria L; Ihrie, Mark D; Ingram, Jennifer LAsthma is a common, chronic airway inflammatory disease marked by airway hyperresponsiveness, inflammation, and remodeling. Asthma incidence has increased rapidly in the past few decades and recent multicenter analyses have revealed several unique asthma endotypes. Of these, type-2 high asthma with comorbid obesity presents a unique clinical challenge marked by increased resistance to standard therapies and exacerbated disease development. The extrinsic coagulation pathway plays a significant role in both type-2 high asthma and obesity. The type-2 high asthma airway is marked by increased procoagulant potential, which is readily activated following damage to airway tissue. In this review, we summarize the current understanding of the role the extrinsic coagulation pathway plays in the airway of type-2 high asthma with comorbid obesity. We propose that asthma control is worsened in obesity as a result of a systemic and local airway shift towards a procoagulant and anti-fibrinolytic environment. Lastly, we hypothesize bariatric surgery as a treatment for improved asthma management in type-2 high asthma with comorbid obesity, facilitated by normalization of systemic procoagulant and pro-inflammatory mediators. A better understanding of attenuated coagulation parameters in the airway following bariatric surgery will advance our knowledge of biomolecular pathways driving asthma pathobiology in patients with obesity.Item Open Access Inflammation triggered by the NLRP3 inflammasome is a critical driver of diabetic bladder dysfunction.(Frontiers in physiology, 2022-01) Hughes, Francis M; Odom, Michael R; Cervantes, Anissa; Purves, J ToddDiabetes is a rapidly expanding epidemic projected to affect as many as 1 in 3 Americans by 2050. This disease is characterized by devastating complications brought about high glucose and metabolic derangement. The most common of these complications is diabetic bladder dysfunction (DBD) and estimates suggest that 50-80% of patients experience this disorder. Unfortunately, the Epidemiology of Diabetes Interventions and Complications Study suggests that strict glucose control does not decrease ones risk for incontinence, although it does decrease the risk of other complications such as retinopathy, nephropathy and neuropathy. Thus, there is a significant unmet need to better understand DBD in order to develop targeted therapies to alleviate patient suffering. Recently, the research community has come to understand that diabetes produces a systemic state of low-level inflammation known as meta-inflammation and attention has focused on a role for the sterile inflammation-inducing structure known as the NLRP3 inflammasome. In this review, we will examine the evidence that NLRP3 plays a central role in inducing DBD and driving its progression towards an underactive phenotype.Item Open Access Inflammatory Th1 and Th17 in the Intestine Are Each Driven by Functionally Specialized Dendritic Cells with Distinct Requirements for MyD88.(Cell Rep, 2016-10-25) Liang, Jie; Huang, Hsin-I; Benzatti, Fernanda P; Karlsson, Amelia B; Zhang, Junyi J; Youssef, Nourhan; Ma, Averil; Hale, Laura P; Hammer, Gianna ENormal dynamics between microbiota and dendritic cells (DCs) support modest numbers of T cells, yet these do not cause inflammation. The DCs that induce inflammatory T cells and the signals that drive this process remain unclear. Here, we demonstrate that small intestine DCs lacking the signaling attenuator A20 induce inflammatory T cells and that the signals perceived and antigen-presenting cell (APC) functions are unique for different DC subsets. Thus, although CD103(+)CD11b(-) DCs exclusively instruct IFNγ(+) T cells, CD103(+)CD11b(+) DCs exclusively instruct IL-17(+) T cells. Surprisingly, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103(-)CD11b(+) DCs instruct both IFNγ(+) and IL-17(+) T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103(-)CD11b(+) and CD103(+)CD11b(+) DCs expand pathologic Th17 cells. Thus, in disease pathogenesis, specific DCs instruct specific inflammatory T cells.Item Open Access Magnetic resonance imaging of graded skeletal muscle injury in live rats.(Environ Health Insights, 2014) Cutlip, Robert G; Hollander, Melinda S; Johnson, G Allan; Johnson, Brice W; Friend, Sherri A; Baker, Brent AINTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses.Item Open Access Patellar skin surface temperature by thermography reflects knee osteoarthritis severity.(Clin Med Insights Arthritis Musculoskelet Disord, 2010-10-15) Denoble, Anna E; Hall, Norine; Pieper, Carl F; Kraus, Virginia BBACKGROUND: Digital infrared thermal imaging is a means of measuring the heat radiated from the skin surface. Our goal was to develop and assess the reproducibility of serial infrared measurements of the knee and to assess the association of knee temperature by region of interest with radiographic severity of knee Osteoarthritis (rOA). METHODS: A total of 30 women (15 Cases with symptomatic knee OA and 15 age-matched Controls without knee pain or knee OA) participated in this study. Infrared imaging was performed with a Meditherm Med2000™ Pro infrared camera. The reproducibility of infrared imaging of the knee was evaluated through determination of intraclass correlation coefficients (ICCs) for temperature measurements from two images performed 6 months apart in Controls whose knee status was not expected to change. The average cutaneous temperature for each of five knee regions of interest was extracted using WinTes software. Knee x-rays were scored for severity of rOA based on the global Kellgren-Lawrence grading scale. RESULTS: The knee infrared thermal imaging procedure used here demonstrated long-term reproducibility with high ICCs (0.50-0.72 for the various regions of interest) in Controls. Cutaneous temperature of the patella (knee cap) yielded a significant correlation with severity of knee rOA (R = 0.594, P = 0.02). CONCLUSION: The skin temperature of the patellar region correlated with x-ray severity of knee OA. This method of infrared knee imaging is reliable and as an objective measure of a sign of inflammation, temperature, indicates an interrelationship of inflammation and structural knee rOA damage.Item Open Access Role of T cells in malnutrition and obesity.(Front Immunol, 2014) Gerriets, Valerie A; MacIver, Nancie JNutritional status is critically important for immune cell function. While obesity is characterized by inflammation that promotes metabolic syndrome including cardiovascular disease and insulin resistance, malnutrition can result in immune cell defects and increased risk of mortality from infectious diseases. T cells play an important role in the immune adaptation to both obesity and malnutrition. T cells in obesity have been shown to have an early and critical role in inducing inflammation, accompanying the accumulation of inflammatory macrophages in obese adipose tissue, which are known to promote insulin resistance. How T cells are recruited to adipose tissue and activated in obesity is a topic of considerable interest. Conversely, T cell number is decreased in malnourished individuals, and T cells in the setting of malnutrition have decreased effector function and proliferative capacity. The adipokine leptin, which is secreted in proportion to adipocyte mass, may have a key role in mediating adipocyte-T cell interactions in both obesity and malnutrition, and has been shown to promote effector T cell function and metabolism while inhibiting regulatory T cell proliferation. Additionally, key molecular signals are involved in T cell metabolic adaptation during nutrient stress; among them, the metabolic regulator AMP kinase and the mammalian target of rapamycin have critical roles in regulating T cell number, function, and metabolism. In summary, understanding how T cell number and function are altered in obesity and malnutrition will lead to better understanding of and treatment for diseases where nutritional status determines clinical outcome.Item Open Access Serum C-Reactive Protein (CRP), Target for Therapy or Trouble?(Biomark Insights, 2007-02-07) Kraus, Virginia B; Jordan, Joanne MHigh sensitivity serum C-reactive protein (hs-CRP) has come into clinical use as a marker of risk for cardiovascular disease (CVD). In addition to a role as a marker of disease, CRP has also been implicated in the pathogenesis of CVD. Specific small-molecule inhibitors of CRP have recently been developed with the intent of mitigating cardiac damage during acute myocardial infarction. However, the use of CRP, both as a risk marker and a disease target are controversial for several reasons. Serum hs-CRP concentrations can be elevated on the basis of genetics, female gender, and non-Caucasian ethnicity. It is not clear, in these contexts, that elevations of hs-CRP have any pathological significance. As a non-specific indicator of inflammation, CRP is also not a specific indicator of a single disease state such as cardiovascular disease but elevated concentrations can be seen in association with other comorbidities including obesity and pulmonary disease. In sharp contrast to the proposed inhibition of CRP for cardiovascular disease treatment, the infusion of CRP has been shown to have profound therapeutic benefits for autoimmune disease and septic shock. The balance between the risks and benefits of these competing views of the role of CRP in disease and disease therapy is reminiscent of the ongoing controversy regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal disease and their cardiovascular side effects. Soon, NSAIDs may not be the only agents about which Rheumatologists and Cardiologists may spar.Item Open Access The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer.(Oncotarget, 2016-04-12) Parsons, Henrique A; Baracos, Vickie E; Hong, David S; Abbruzzese, James; Bruera, Eduardo; Kurzrock, RazelleBACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.Item Embargo The Role of UBE2N in Skin Homeostasis and Inflammation(2024) Lee, Min JinUbiquitination is a post-translational modification that mediates protein stability and function, and it is implicated in almost every aspect of cellular activities. UBE2N is an E2 conjugating enzyme that mediates Lys-63 (K63) polyubiquitination. It plays essential roles in signal transduction and DNA repair mechanisms. In this thesis, we utilized two conditional mouse models to investigate the role of UBE2N in the skin: Rosa26CreER.Ube2nfl/fl and Krt5CreER.Ube2nfl/fl. We found that the conditional deletion of Ube2n in adult skin resulted in inflammatory skin defects. Using histology, single-cell RNA-sequencing, RT-qPCR, flow cytometry, immunofluorescent staining, and western blotting, we learned that the inflammatory skin accompanied epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration. The skin expressed a pro-inflammatory gene signature including elevated levels of cytokines such as Il1 and Il24 and chemokines such as Cxcl1 and Cxcl2. The immune infiltration was primarily of myeloid origin including neutrophils and M1-like proinflammatory macrophages. Using the basal keratinocyte-specific Krt5CreER.Ube2nfl/fl transgenic mouse model, we also learned that loss of UBE2N in keratinocytes is sufficient to induce inflammatory skin defects that was observed in the Rosa26CreER.Ube2nfl/fl mice. The Ube2n knockout (KO) keratinocytes also showed increased levels of pro-inflammatory cytokine and myeloid cell chemokine genes. Consistently, the Ube2n KO skin showed infiltration of myeloid cells. Furthermore, we discovered that genes in the IL-1 signaling pathway are highly upregulated in both the Rosa26CreER.Ube2nfl/fl and the Krt5CreER.Ube2nfl/fl. Of them, interleukin-1 receptor-associated kinase 1 (IRAK1) was activated in the Ube2n KO skin. To test the hypothesis that the loss of Ube2n induced inflammatory phenotypes are mediated by IL-1 signaling pathway, we treated Krt5CreER.Ube2nfl/fl mice with an IRAK1 and 4 (IRAK1/4)-specific pharmacological inhibitor. The IRAK1/4 inhibitor reduced the level of inflammatory phenotypes of the Ube2n KO skin. This suggested that IRAK1/4 signaling pathway plays an important role in mediating the inflammation caused by loss of Ube2n. Many chronic inflammatory skin disorders are accompanied by cutaneous dysbiosis. Since loss of UBE2N led to inflammatory skin lesions with disrupted epidermis and increased pro-inflammatory immune signature, we also investigated whether UBE2N plays a role in cutaneous microbial regulation. In order to assess the cutaneous microbiome of the Ube2n KO skin, we performed an amplicon sequencing analysis of the V4 region of 16S rRNA gene from skin swabs of the and the control mice. The sequencing data showed that there was a dramatic shift in microbial population: an increased abundance of Corynebacterium in the inflamed Ube2n KO skin. In summary, our investigation of the role of UBE2N and its function in the skin revealed that it is critical for maintaining epidermal homeostasis and suppression of skin inflammation. We also learned that UBE2N loss-of-function-mediated skin inflammation leads to dysbiosis. This suggests that the restoration of UBE2N signaling and/or IRAK1/4 inhibition could be potential therapeutic strategies for inflammatory skin disorders and controlling healthy skin microbiome.
Item Open Access Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain.(The journal of pain, 2023-04) Scarneo, Scott; Zhang, Xin; Wang, Yaomin; Camacho-Domenech, Jose; Ricano, Jennifer; Hughes, Philip; Haystead, Tim; Nackley, Andrea GThe origin of chronic pain is linked to inflammation, characterized by increased levels of pro-inflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of pro-inflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the COMT inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the dorsal root ganglia of Gcamp3 mice. In all three models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of pro-inflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments.