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NLRP3 is a BMI-independent mediator of stable COPD

BMC Pulmonary Medicine volume 25, Article number: 31 (2025) Cite this article

Abstract

Purpose

The inflammatory response in animal models of chronic obstructive pulmonary disease (COPD) is activated by the NLR-family-pyrin-domain-containing-3 (NLRP3) inflammasome pathway, which is also known to play a role in obesity-related inflammation. The NLRP3/caspase-1/interleukin (IL)-1β pathway might be involved in the progression of COPD with increasing body mass index. To our knowledge, no previous studies have explored the role of NLRP3 inflammasome markers in linking COPD and obesity. Here, we aim to investigate this potential connection by examining levels of NLRP3, caspase-1, IL-1β, and IL-17A and to provide additional data on the expression of these molecules in relation to smoking status and COPD severity.

Methods

A case‒control study was conducted between July 2020 and March 2023. Peripheral blood mononuclear cells were isolated, and total RNA was extracted for real-time quantitative polymerase chain reaction (qPCR) analysis to measure the expression levels of inflammasome molecules.

Results

29 subjects who were diagnosed with stable COPD and 32 controls were included in the data analysis. NLRP3 and IL-17A but not caspase-1 or IL-1β expression was significantly greater in the COPD group than in the control group. We detected a significant increase in NLRP3 levels in the smoker COPD group (p = 0.009) and nonsmoker COPD group (p = 0.045) compared with those in the nonsmoker control group. There was no significant correlation between BMI and the inflammasome markers.

Conclusion

As proinflammatory biomarkers, NLRP3 and IL-17A are prominent in stable COPD patients. Smoking may trigger NLRP3-mediated inflammation in stable COPD patients. The expression levels of NLRP3 inflammasome molecules did not differ in terms of disease severity or BMI.

Graphical Abstract

Peer Review reports

Introduction

Chronic obstructive pulmonary disease (COPD) is a chronic airway disease and the fourth leading cause of mortality worldwide, accounting for 3.5 million deaths in 2021 according to World Health Organization [1, 2]. It is characterized by respiratory symptoms and persistent airflow obstruction caused by oxidative stress and various inflammatory mechanisms [1, 3]. The molecular mechanisms underlying COPD-related inflammation involve both innate and adaptive immunity, with neutrophils, macrophages, and lymphocytes playing pivotal roles [3]. Several questions remain unanswered, including the outcomes of inflammation, clinical phenotypes, prognosis, and treatment response.

Inflammasome multiprotein signaling complexes and the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers procaspase-1 cleavage to form caspase-1, which mediates the conversion of interleukin (IL)-1β and IL-18 to their active forms [4]. Following sequential proteolytic cleavage, IL-1β and IL-18 activation results in neutrophil recruitment, cell damage, and apoptosis, triggering other inflammatory pathways [4]. The upregulation of the NLRP3 pathway enhances adaptive immune responses, such as the T helper (Th)-17/IL-17 axis, which contributes to neutrophilic inflammation, the dominant pathway responsible for the production of key mediators of inflammatory changes in the airways of COPD patients [5, 6]. Recent data suggest that NLRP3 inflammasome activation might be linked to COPD pathogenesis [7]. In vitro and in vivo studies have shown that NLRP3 knockdown in COPD models reduces IL-18, IL-1β, neutrophil, macrophage, lymphocyte levels and lung inflammation [3].

Obesity, another disease characterized by complex systemic inflammation, has been linked to the transformation of a proinflammatory state from an anti-inflammatory state due to changes in the adipokine balance [8]. In obese patients, NLRP3 is overexpressed in subcutaneous adipose tissue [9] and visceral adipose tissue [10]. It is a critical component of the innate immune system and has harmful proinflammatory effects on both adipose and lung tissue; therefore, it is thought to play an important role in obesity [11]. Studies have demonstrated that NLRP3-deficient mice fail to develop obesity, insulin resistance, and cardiac damage when fed a high-fat diet [12]. These protective effects have been linked to the activation of autophagy [13]. Furthermore, NLRP3 knockout has been shown to significantly extend the lifespan of obese mice [14]. High-fat diets, on the other hand, have been reported to increase NLRP3 expression, with the NLRP3-caspase-1 pathway proposed as a key regulator in adipocyte differentiation, driving a more insulin-resistant phenotype [15]. However, the literature presents contradictory findings regarding NLRP3 expression. While Goossens et al. (2012) observed no significant differences in NLRP3 expression between obese and lean subjects, other studies have reported upregulated NLRP3 levels in obesity [16,17,18,19].

The relationship between obesity and COPD is further underscored by the obesity paradox, which describes an inverse association between body mass index (BMI) and all-cause mortality in COPD patients. Overweight and obese individuals with COPD exhibit improved survival compared to their normal-weight counterparts [20]. This paradox may reflect protective metabolic or inflammatory effects of obesity mediated through NLRP3 regulation. For example, obesity-related increases in NLRP3 activation in adipose tissue could lead to immune signaling changes that impact lung inflammation, thereby modifying COPD outcomes. However, the molecular mechanisms underlying this paradox remain poorly understood.

In this study, our objective is to examine how COPD and adiposity correlate with the levels of NLRP3, caspase-1, IL-1β, and IL-17A. Additionally, we aim to present supplementary findings regarding the expression levels of these molecules concerning smoking habits and the severity of COPD.

Materials/methods

Study design and population

This single-center, case-control study was conducted at the Dokuz Eylul University (DEU) Pulmonary Medicine Outpatient Clinic and İzmir Biomedicine and Genome Center between July 2020 and March 2023, with 29 COPD patients and 32 control volunteers aged 40 to 80 years. Individuals who were being followed up for COPD and had post-bronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio < 70% were invited to the study to be included in the COPD group. The control group was participants who applied to our outpatient clinic but had not been diagnosed as COPD or other pulmonary diseases. Participants gave both verbal and written consent to be included to the study. Individuals who had any other known lung disease, autoinflammatory diseases, immunosuppression, systemic steroid or antibiotic usage, or acute exacerbation of COPD (AECOPD) in the previous month were excluded.

COPD diagnosis and GOLD classification

The COPD group was defined based on clinical and spirometric evaluation. COPD patients previously categorized according to the ABCD assessment tool have been revised into 3 groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 assessment, which is based on exacerbations independent of the level of symptoms. A and B groups remain unchanged, whereas the former C and D groups are now called the “E” group, with a history of either two or more moderate exacerbations or any severe exacerbation (defined as one requiring hospitalization) in the previous year, irrespective of symptom burden [1].

Body mass index and body composition measurement

The body weight, fat, and water ratios of the participants were measured with the TANITA TBF-300 device. Height measurements were calculated via a portable stadiometer while the volunteers were upright and barefoot. Body mass index (BMI) was calculated with the formula weight (kg)/height (m2). Subjects with a body mass index less than 30 kg/m2 were considered nonobese, and those with a BMI of 30 kg/m2 and above were considered obese. Participants were further categorized into BMI-based subgroups (nonobese and obese) to allow for a more detailed analysis of the relationship between BMI and COPD. These subgroups were used to compare inflammatory marker levels within each BMI category between control and COPD groups.

Isolation of Peripheral Blood mononuclear cells

4 cc of peripheral venous blood were collected in K2 EDTA tubes (BD Vacutainer®, USA), and peripheral blood mononuclear cells (PBMCs) were isolated within 2 h via the density gradient separation method as previously described [21]. The collected PBMCs were stored at -80 °C in TriZOL.

Relative gene expression analysis

RNA isolation was performed with a Direct-zol RNA Miniprep Kit (Zymo Research, USA). The quantity and purity of the RNA samples were measured via a NanoDrop™ 2000/2000c Spectrophotometer (Thermo Fisher Scientific, USA). Samples with A260/280 ratios less than 1.7 were omitted. cDNA synthesis was performed with a First Strand cDNA Synthesis Kit (Zymo Research, USA). The reactions were carried out using Gotaq Qpcr Master Mix (Promega, USA) and a 7500 Fast Real-Time PCR device (Applied Biosystems, USA). All reactions were performed in three technical replicates. The standard cycle conditions for the analysis were set according to the manufacturer’s instructions. The cycle threshold (Ct) ​​and relative quantification (RQ) values were calculated as previously described [22]. The undetected Ct values were set to the maximum value of 40 [23].

Statistical analysis

Normality was assessed via the Shapiro‒Wilk test. Normally distributed continuous variables were analyzed with a two-tailed t-test and are presented as mean ± SD. Continuous variables that were nonnormally distributed are presented as median and 25–75 interquartile range (IQR) and they were compared via the Mann‒Whitney U test. Fisher’s exact test was used for categorical variables. p-values less than 0.05 were considered significant. Statistical analyses were conducted via R Studio (version 2022.02.3).

Results

Baseline characteristics

29 stable COPD patients and 32 control subjects were included in the current study. There was no significant difference in sex distribution or active smoking status between the groups (Table 1). The control group was significantly younger than the COPD group (54 ± 9 years vs. 66 ± 12 years, p < 0.001). The number of smoking pack-years was significantly greater in the COPD group (p < 0.001). The control group had significantly higher weight (83.4 ± 15.6 vs. 73.6 ± 20.8, respectively, p = 0.049) and BMI (median (IQR): 30.2 (6.8) vs. 26.8 (7.7), respectively, p = 0.048) than did the COPD group. The waist‒hip measurements, body composition analysis, and demographic profiles of the study groups are presented in detail in Table 1.

Table 1 Baseline characteristics of the COPD and control groups
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RQ of NLRP3, IL-17A, IL-1β, and Caspase-1 in the COPD and Control Groups

RQ scores of inflammasome markers were used to compare their expression in the COPD and control groups, as presented in Fig. 1; Table 2. NLRP3 and IL-17A expression was significantly higher in those with COPD than in those without COPD (p = 0.018 and p = 0.032, respectively). IL-1β and caspase-1 expression did not significantly differ between the COPD and control groups (p = 0.083 and p = 0.107, respectively) (Fig. 1; Table 2).

Fig. 1
figure 1

RQ scores of caspase-1, IL-1β, IL-17A, and NLRP3 between the COPD and control groups. The Mann‒Whitney U test was used to analyze the data. p values ≤ 0.05 were considered statistically significant. (N.S.: not significant, *p ≤ 0.05)

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Table 2 RQ scores of each marker in the COPD and control groups
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The participants were stratified into three categories based on GOLD assessment, and the expression levels of inflammasome markers were compared between these groups, as shown in Fig. 2; Table 3. In the GOLD A group (n=5), caspase-1 levels were significantly higher than the controls (median [IQR]: 2.93 [1.21] vs. 1.06 [1.69], p = 0.010). However, the levels of IL-1β, IL-17A, and NLRP3 were not significantly different between COPD patients and controls (p = 0.088, p = 0.073, p = 0.435, respectively). In the GOLD B group (n = 12), caspase-1 and NLRP3 levels were significantly higher in COPD patients than in controls (p = 0.014 and p = 0.008, respectively), whereas IL-1β and IL-17A levels were not significantly different (p = 0.154 and p = 0.091). No significant differences were observed in the GOLD E group (n = 12) (Fig. 2; Table 3).

Fig. 2
figure 2

RQ scores of NLRP3 inflammasome markers based on GOLD classification. The Mann‒Whitney U test was used to analyze the data. p-values ≤ 0.05 were considered statistically significant (**p ≤ 0.01). Non-significant values are not indicated in the graph. (Sample sizes: control (n=32), GOLD A (n=5), GOLD B (n=12), GOLD E (n=12))

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Table 3 RQ scores of each marker grouped according to GOLD classification
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Smoking status and COPD

Participants were evaluated based on their smoking status to assess the effect of cigarette smoking on inflammatory markers. No significant difference in IL-17A expression was observed between the COPD and control groups in terms of smoking status (Table 4). However, IL-1β mRNA levels were significantly higher in the nonsmoker COPD (nsCOPD) group than in the nonsmoker control (nsCONT) group (p = 0.016), but no significant differences were found in the smoker COPD (sCOPD) group vs. the smoker control (sCONT) group (p = 0.927), the sCOPD group vs. the nsCONT group (p = 0.791), or the nsCOPD group vs. the sCONT group (p = 0.162). NLRP3 expression was significantly higher in the sCOPD group than in the nsCONT group and in the nsCOPD group than in the nsCONT group (p = 0.009 and p = 0.045, respectively). The sCOPD and sCONT groups, or the nsCOPD and sCONT groups did not differ significantly (p = 0.101 and p = 0.287, respectively). Additionally, no significant difference in NLRP3 expression was found between the sCONT and nsCONT groups (p = 0.528, data not shown).

Table 4 RQ scores of each group (upper table) and significance of differences in the expression levels (lower table) of each marker grouped by the smoking status of the subjects
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BMI and inflammasome markers

NLRP3 expression in the nonobese COPD group was significantly higher than that in the nonobese control group (p = 0.039). Overall, we did not find any correlation between BMI and the expression of any of the evaluated molecules in the COPD group (Table 5).

Table 5 COPD and control subjects are grouped according to their BMI
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Discussion

In our study, we compared the NLRP3 inflammasome pathway elements between stable COPD patients and controls. NLRP3 and IL-17A expression was greater in the stable COPD group than in the control group. However, there was no significant difference in the levels of IL-1β and caspase-1 between the groups.

Our finding of IL-17A expression is in line with the current literature [24, 25]. We detected increased NLRP3 expression in the collected PBMCs of subjects with stable COPD. There are opposing observations in the literature regarding the NLRP3 expression levels in COPD patients. In a study by Di Stefano, there was no significant difference in NLRP3 expression in the bronchial epithelium of stable COPD patients [26]. On the other hand, Fu et al. reported significantly increased NLRP3 expression in the sputum of stable COPD patients, whereas they did not find any difference in the blood samples [27]. Faner et al. reported increased NLRP3 expression in the lung tissue of stable COPD patients [28], whereas Markelić et al. reported this increase in the PBMCs of COPD patients [29].

There are contradictory data in the literature concerning the expression levels of IL-1β and caspase-1. Markelić et al. reported that the levels of IL-1β and caspase-1 were significantly higher in the PBMCs of COPD patients [29], whereas Di Stefano et al. reported that they were similar in the bronchial submucosa of stable COPD patients and control individuals [26]. Yi et al. demonstrated that IL-1β levels were significantly increased in the small airway epithelium but not in lung tissue, sputum, or blood samples [30]. Wang et al. reported that the expression levels of NLRP3, caspase-1, and IL-1β were significantly increased in AECOPD patients and significantly reduced in stable COPD patients [31]. Considering that caspase-1 and IL-1β were also increased in healthy smokers, the expression in the COPD and control groups might be balanced due to the smoking status [32, 33]. Overall, these results suggest that caspase-1 and IL-1β expression do not differ in the serum of stable COPD patients and controls, but smoking status in the control group may result in misinterpretation. It’s essential to note that this study measured only the mRNA levels of these molecules. However, mRNA expression changes do not always correlate with protein level changes, highlighting the need for further research to understand the actual protein dynamics and their impact on COPD pathogenesis [34].

The expression levels of inflammasome markers were stratified by smoking status. There was no significant difference in IL 17-A expression according to smoking status. According to Lee et al., other cytokines should be considered to link IL-17A levels with pathogenicity [35]. We did not observe any effect of smoking on caspase-1 levels in any pairwise comparison. In line with our results, Di Stefano et al. did not report a significant difference in caspase-1 levels in the bronchial epithelium of groups with different smoking statuses [26].

IL-1β mRNA levels were significantly higher only in the nonsmoker COPD (nsCOPD) group than in the nonsmoker control (nsCONT) group. Interestingly, no significant difference was found among the other groups. This might be due to the small sample size. Some studies suggest that IL-1β levels in the lungs increase with smoking in COPD patients as well as in healthy subjects [32, 36]. The data from animal models of COPD further support that cigarette smoke elevates IL-1β levels [37]. However, Di Stefano et al. did not reveal a significant difference in IL-1β levels according to the smoking status of stable COPD patients and concluded that increased levels of inflammasome markers might be related to the exacerbation of COPD [26].

NLRP3 expression was significantly higher in the smoker COPD (sCOPD) and nsCOPD groups than in the nsCONT group. However, NLRP3 expression in the sCOPD and nsCOPD groups did not differ from that in the smoker control (sCONT) group. In line with our results, Markelić et al. demonstrated that NLRP3 expression was significantly higher in the COPD group than in the control group and that this expression was strongly correlated with the smoking status of the subjects [29]. Similarly, Wang et al. reported similar results in mouse models of COPD [38]. Together, our results suggest that smoking status may promote NLRP3-mediated COPD inflammation.

NLRP3 levels were significatly higher in the GOLD B group, whereas caspase-1 levels were greater in both the GOLD A and GOLD B groups. ​​These results indicate that both the NLRP3 inflammasome and its end products are increased in COPD patients, regardless of the severity and number of exacerbations, or that the NLRP3 pathway is not dominant in the group characterized by exacerbations. In line with our results, Di Stefano and colleagues concluded that the levels of innate immune mediators, but not the levels of NLRP3 inflammasome molecules, increase with the severity of stable COPD [26]. Additionally, Markelić et al. did not find a significant increase in the expression of IL-1β, NLRP3 or caspase-1 with increasing severity of airway obstruction in COPD patients [29]. Together, our results indicate that NLRP3 inflammasome marker expression does not correlate with the severity of the disease.

We did not find any relationship between obesity and COPD through the NLRP3 pathway. The impact of BMI on COPD has been widely studied, with findings suggesting that being overweight is associated with a lower risk of COPD, whereas being underweight may increase the risk [39]. Other studies have shown that being underweight or obese can increase the risk of chronic inflammatory airway diseases [40]. Palma et al. reported that NLRP3 inflammasome activation might play a key role in promoting lung disease in obesity [11]. Given that obesity and COPD are hypothesized to share similar inflammatory pathways involving NLRP3, we investigated the effect of BMI on COPD pathogenesis. We found that NLRP3 expression was significantly higher only in nonobese COPD patients than in controls, irrespective of fat-free mass. However, there was no difference in the levels of caspase-1, IL-1β, IL-17A, or NLRP3 between the COPD group and the control group or within the COPD group, as measured by BMI. This lack of difference might be due to the previously noted association between being nonobese and COPD, suggesting that the NLRP3 pathway is particularly prominent in this subset of patients. However, it has also been claimed that the obesity paradox is absent among never smokers with COPD [41]. In our study, we only observed differences in nonobese and smoker COPD patients compared with controls within our relatively small sample size. Notably, our study included stable COPD patients, and NLRP3 pathway mRNAs may have been degraded due to a lack of exacerbation over time. Further studies with AECOPD patients and larger sample sizes might be helpful to elucidate the relationship between COPD and obesity.

Conclusion

In this study, we compared the expression levels of NLRP3 inflammasome markers in stable COPD patients and control subjects, considering their smoking status, COPD severity, and BMI. Our results indicate that the levels of NLRP3 and IL-17A, but not those of IL-1β or caspase-1, are significantly elevated in the PBMCs of stable COPD patients. The increase in NLRP3 expression was particularly notable in smokers and nonobese patients, both of which are associated with chronic inflammatory lung diseases. Furthermore, we found that NLRP3 levels were significantly higher in both the active smoking and nonsmoking COPD groups than in the nonsmoking control group, with the increase being more pronounced in the active smoking COPD group. These findings suggest that smoking may trigger NLRP3-mediated inflammation in stable COPD patients. We did not observe a significant difference between the levels of NLRP3 inflammasome markers and obesity. This may be due to the inclusion of stable COPD patients in our study, who had not experienced an exacerbation for more than a month. Further studies with larger sample sizes are needed to elucidate the molecular mechanisms underlying the relationships among obesity, cigarette smoking, and COPD.

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on request.

Abbreviations

AECOPD:

Acute exacerbation of COPD

BMI:

Body mass index

COPD:

Chronic obstructive pulmonary disease

Ct:

Cycle threshold

NLRP3:

NLR-family-pyrin-domain-containing-3

nsCONT:

Nonsmoker control group

nsCOPD:

Nonsmoker COPD group

PBMC:

Peripheral blood mononuclear cells

RQ:

Relative quantification

qPCR:

Real-time quantitative polymerase chain reaction

sCONT:

Smoker control group

sCOPD:

Smoker COPD group

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Acknowledgements

The authors would like to acknowledge the Turkish Thoracic Society for the support and express their gratitude to all study participants for their contributions.

Funding

This study was supported by the Turkish Thoracic Society (Funding no: Y-144/2020).

Author information

Authors and Affiliations

  1. İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Türkiye

    Yonca Gungor & Hulya Ayar Kayali

  2. İzmir Biomedicine and Genome Center, İzmir, Türkiye

    Yonca Gungor, Yiğit Kozalı & Hulya Ayar Kayali

  3. Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Selin Ercan & Saliha Selin Özuygur Ermiş

  4. Department of Biotechnology, The Graduate School of Natural and Applied Sciences, Dokuz Eylul University, İzmir, Türkiye

    Yiğit Kozalı

  5. ERFARMA Drug Application and Research Center, Erciyes University, Kayseri, Türkiye

    Gizem Kursunluoglu

  6. Department of Public Health, Dokuz Eylul University, İzmir, Türkiye

    Ceyda Sahan

  7. Department of Chest Diseases, Faculty of Medicine, Dokuz Eylül University, İzmir, Türkiye

    Aylin Ozgen Alpaydin

  8. Department of Chemistry, Division of Biochemistry, Faculty of Science, Dokuz Eylul University, İzmir, Türkiye

    Hulya Ayar Kayali

Authors
  1. Yonca Gungor
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  2. Selin Ercan
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  3. Saliha Selin Özuygur Ermiş
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  4. Yiğit Kozalı
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  5. Gizem Kursunluoglu
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  6. Ceyda Sahan
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  7. Aylin Ozgen Alpaydin
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  8. Hulya Ayar Kayali
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Contributions

H.A.K. and A.O.A. conceptualized the study design and supervised the experiments. H.A.K., A.O.A., C.S., G.K., S.E. and S.S.Ö.E. participated in writing the project proposal and applying for ethical approval. S.E. and S.S.Ö.E. collected the samples. Y.G. and Y.K. designed and conducted the experiments. A.O.A., Y.G., S.E., and S.S.Ö.E. wrote the manuscript. Y.G. performed the statistical analyses and prepared the figures and tables. A.O.A. and Y.G. interpreted the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Aylin Ozgen Alpaydin or Hulya Ayar Kayali.

Ethics declarations

Ethical approval

The study was approved by the local ethics committee of Dokuz Eylul University (No: 2020/01–23, date: 6 January 2020).

Consent to participate

Verbal and written informed consent to participate in this study was obtained from all individual participants.

Consent to publish

Not Applicable: this manuscript does not include identifying images or other personal or clinical details of participants that compromise anonymity.

Competing interests

The authors declare no competing interests.

Strengths and limitations

To our knowledge, this study is among the first to investigate the impact of obesity on the NLRP3 pathway in COPD. Additionally, owing to the close proximity of our research center, blood samples were analyzed shortly after collection, ensuring data accuracy. However, our study has several limitations. This study was conducted at a tertiary care center with a small sample size, which may not accurately represent the broader COPD population. Moreover, our sample group consisted solely of stable COPD patients, which could limit the assessment of the relationship between obesity and COPD. We also acknowledge age and sex distribution limitations within the sample, which may affect the generalizability of our findings. As no exacerbations were observed for at least one month prior, potential variations in inflammasome expression linked to exacerbation periods may not have been detected. Future studies should investigate these effects during exacerbation phases and aim for a larger, multi-center cohort with balanced age and sex distribution for a more comprehensive understanding of the NLRP3 pathway’s role.

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Gungor, Y., Ercan, S., Ermiş, S.S.Ö. et al. NLRP3 is a BMI-independent mediator of stable COPD. BMC Pulm Med 25, 31 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-024-03435-6

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Keywords

BMC Pulmonary Medicine

ISSN: 1471-2466

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