Sex-Specific Signature in the Circulating NLRP3 Levels of Saudi Adults with Metabolic Syndrome

Abstract

Recently, inflammasomes such as NLRP3 as cytosolic pattern-recognition receptors have been implicated in the development of inflammation; however, limited investigations report the circulating levels of this protein. The objective, thus, was to investigative circulating NLRP3 levels in Saudi patients with a low-grade inflammatory disorder called metabolic syndrome (MetS). Two hundred Saudi adults aged 30–65, with or without MetS diagnosed on the basis of National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) criteria, were randomly recruited. Five MetS components were established according to the diagnostic criteria in the study subjects. Circulating levels of NLRP3 and known inflammation markers, such as tumor necrosis factor α (TNF-α), C-reactive protein (CRP) and interleukins (IL-1β and IL-18), were measured in the blood samples taken from the study subjects. Gender-based analysis showed a significant elevated circulating levels of NLRP3 in non-MetS men compared to non-MetS females (p < 0.001). Moreover, an increase in circulating levels of NLRP3 with a number of MetS components (p = 0.038) was observed only in females. A significant positive correlation of NLRP3 levels with age (r = 0.20, p = 0.04), BMI (r = 0.32, p < 0.01) and waist (r = 0.24, p = 0.02) and a significant negative correlation between NLRP3 and HDL-cholesterol (r= −0.21, p = 0.03) were also observed in females. Logistic regression analysis also yielded a sex-specific positive association of NLRP3 with MetS in females, with this association influenced mostly by central obesity and dyslipidemia components of MetS. In conclusion, this study suggests a sexual disparity in the circulating levels of NLRP3, with a trend of increasing circulating NLRP3 levels with increasing MetS components observed only in females, influenced mostly by adiposity and dyslipidemia components of MetS. Longitudinal studies with a larger sample size and investigating sex-specific hormones with NLRP3 would be needed to establish a causal relationship of NLRP3 with MetS.

Acute Glycemic Control in Prediabetes Individuals Favorably Alters Serum NLRP3 Inflammasome and Related Interleukins

“…Conforming to this hypothesis, the current longitudinal study found an inverse association between HDL cholesterol levels and NLRP3. This is consistent with our previous findings [ 42 ]. These results are of great significance, as obesity is an important contributing factor in diabetes and this could be seen in this study, in which the weight of the PD group that developed T2DM was already higher than those of the PD group that reverted to normal and the group that remained PD.…”

The role of interleukin-1β in type 2 diabetes mellitus: A systematic review and meta-analysis

“…Obesity is linked to low-grade systemic inflammation that progresses to metabolic diseases as well as insulin resistance accompanied by altered resident immune cells in adipose tissue ( 38 ). Obese patients have an upregulation in NLRP3 and IL-1β expression in intra-abdominal and sub-cutaneous fat and this was confirmed by genetic analysis ( 39 – 41 ), eventually leading to NLRP3 inflammasome activation and caspase-1mediated IL-1β and IL-18 secretion and pyroptosis ( 38 ). Pyroptosis is an inflammatory type of programmed cell death that is crucial for IL‐1β release because it lacks a signal sequence for exocytosis ( 42 ).…”

“…Managing weight and calory intake can contradict this upregulation. Hence, implying that obesity induced insulin resistance (IR) and NLRP3 inflammasome activation are interconnected ( 39 – 41 ). Vandanmagsar et al.…”

Altered insulin secretion dynamics relate to oxidative stress and inflammasome activation in children with obesity and insulin resistance

“…Probably, as an effect of gasdermin-D mediated pyroptotic PBMCs death, this resulted in higher levels of NLRP3 and IL-1β in plasma as well. Circulating levels of NLRP3 have been associated with MS components [ 46 ] and other pathologies in which it may serve as a predictive biomarker [ 47 , 48 ]. This pathological mechanism could at least partially explain the reduced white blood cell counts in this group and therefore, the lower levels of inflammation markers in the LP-OBIR group.…”