Dysregulation of Components of the Inflammasome Machinery After Bariatric Surgery: Novel Targets for a Chronic Disease

Abstract

Background Obesity is a metabolic-chronic disease with important associated morbidities and mortality. Bariatric-surgery is the most effective treatment for maintaining long-term weight-loss in severe obesity and consequently for decreasing obesity-related complications, including chronic inflammation. Aim To explore changes in components of the inflammasome-machinery after bariatric-surgery and their relations with clinical/biochemical-parameters at baseline and six-months after bariatric-surgery. Patients and methods 22 patients with morbid-obesity that underwent bariatric-surgery (sleeve-gastrectomy and roux-en-Y gastric bypass) were included. Epidemiological/clinical/anthropometric/biochemical evaluation was performed at baseline and six-months after bariatric-surgery. Inflammasome-components and inflammatory-associated factors [NOD-like-receptors (NLRs); inflammasome-activation-components; cytokines and inflammation/apoptosis-related components; and cell-cycle and DNA-damage regulators) were evaluated in peripheral-blood mononuclear-cells (PBMCs) at baseline and six-months after bariatric-surgery. Clinical-molecular correlations/associations were analyzed. Functional parameters (lipid-accumulation/viability/apoptosis) were analyzed in response to specific inflammasome-components silencing in liver HEPG2-cells-). Results A profound dysregulation of inflammasome-components after bariatric-surgery was found, especially in NOD-like-receptors, cell-cycle and DNA-damage regulators. Several components were associated to baseline metabolic comorbidities including type-2-diabetes (CCL2/CXCR1/SIRT1), hypertension (AIM2/ASC/P2RX7) and dyslipidemia (CXCL3/NLRP7), and displayed changes in their molecular profile six-months after bariatric-surgery. Gene-expression fingerprint of certain factors (NLRC4/NLRP12/CXCL3/CCL8/TLR4) accurately differentiated pre- and post-operative PBMCs. Most changes were independent of the performed surgical technique. Silencing of NLRC4/NLRP12- resulted in altered lipid-accumulation, apoptosis-rate and cell-viability in HEPG2-cells. Conclusion Bariatric-surgery induces a profound alteration in gene-expression pattern of components of the inflammasome-machinery in PBMCs. Expression and changes of certain inflammasome-components are associated to baseline metabolic comorbidities, including type-2-diabetes, and may be related to the improvement and reversion of some obesity-related comorbidities after bariatric-surgery.

Morphofunctional and Molecular Assessment of Nutritional Status in Head and Neck Cancer Patients Undergoing Systemic Treatment: Role of Inflammasome in Clinical Nutrition

“…A 48.48 Dynamic Array based on microfluidic technology (Fluidigm, San Francisco, CA, USA) was developed and implemented to determine, simultaneously, the expression of 48 transcripts in 45 samples, following the same methods recently described [13,25]. Specific primers for human transcripts of the inflammasome machinery, including NLR-/NOD-like receptors (n = 7), regulators of inflammasome activation (n = 15), cytokines and inflammation/apoptosis-related components (n = 18) as well as cell-cycle and DNAdamage regulators (n = 5) have been specifically designed and validated as previously reported [26]. In addition, three housekeeping genes were used.…”

“…Preamplification, exonuclease treatment and qPCR dynamic array based on microfluidic technology were implemented following the manufacturer's instructions using the Biomark System and the Real-Time PCR Analysis Software 3.0 (Fluidigm), as previously described [26][27][28]. The expression level of each transcript was adjusted by a normalization factor (NF) obtained from the expression levels of two different housekeeping genes (beta actin (ACTB) and glyceraldehyde−3-phosphate dehydrogenase (GAPDH)) using Genorm 3.3.…”

Inflammasomes: Cause or consequence of obesity‐associated comorbidities in humans

“…In contrast, a study reported that NLRP3 expression in SAT, VAT, and liver of 21 patients is not affected by weight loss after 6 months of laparoscopic adjustable gastric banding (despite a decrease in the expression of IL‐1β) [105]. No other studies evaluated the effect of inflammasomes, diet, and weight loss in humans [106].…”

Single Nucleotide Polymorphisms of NLRP12 Gene and Association with Psoriasis

“…The available studies demonstrated NLRP12 implicated in hypertension, obesity, metabolic syndrome, in ammatory bowel disease, alcoholic liver injury, depression [6,[11][12][13][14]. Shared genetic factors, overlapping chronic in ammatory processes, and abnormal immunomodulatory mechanisms may contribute to the multiple comorbidities of psoriasis.…”

“…NLRP12 is primarily expressed in myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, comprising of a central nucleotidebinding domain (NBD), an N-terminal pyrin domain (PYD), and a C-terminal leucine-rich repeat (LRR) domain [8]. NLRP12 can participate in in ammasome-mediated in ammation or function as a negative regulator to suppress in ammation, distinguishing it from other members of the NLR family and conferring upon it a dual role in modulating in ammatory responses [9,10].The available studies demonstrated NLRP12 implicated in hypertension, obesity, metabolic syndrome, in ammatory bowel disease, alcoholic liver injury, depression [6,[11][12][13][14]. Shared genetic factors, overlapping chronic in ammatory processes, and abnormal immunomodulatory mechanisms may contribute to the multiple comorbidities of psoriasis.…”