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.
Highlights
One of the best known among these cytoplasmic pattern recognition receptors (PRR) is the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), which consists of big multiprotein clusters that get activated by a variety of causes, leading to infection resolution while having a part in the pathology of cancer [7], inflammatory disorders [8] and autoimmune disorders [9]
The circulating levels of inflammatory markers (TNF-α, C-reactive protein (CRP) and IL-1β) showed an expected trend of elevated levels in groups with higher metabolic syndrome (MetS) components (p < 0.01 in all); for circulating NLRP3 levels, this trend was missing when all subjects were taken into consideration in Table 1 (p = 0.44)
This study suggests a sexual disparity in the circulating levels of NLRP3 in Saudi men and women, with a trend of increasing circulating NLRP3 levels with increasing MetS components observed only in females
Summary
The identification of germline-encoded pattern recognition receptors (PRR), which recognizes pathogen- and danger-associated molecular patterns (PAMPs and DAMPs), triggers inflammation by stimulating downstream signaling cascades and immune responses initiated in immune cells such as macrophage and dendritic cells [4] PAMPs, such as bacterial endotoxin, are derived from microorganisms, while DAMPs are derived from host cells, including tumor cells, dead cells and compounds produced in response to signals [5] When these PRRs are present in the cytoplasm, they have been attributed to the detection of endogenous danger signals, which leads to the development of inflammation [6]. Inflammasomes, such as NLRP3, form an arm of the innate immune system by mediating the activation of caspase-1 and pro-inflammatory cytokines (IL-1β and IL-18), leading to a cascade of inflammatory processes which, if unchecked, may result in systemic inflammation, a root-cause of metabolic disorders, such as insulin resistance, diabetes, atherosclerosis, etc. [10,11]
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