The Important Role of Phosphatidylserine, ADAM17, TNF-Alpha, and Soluble MER on Efferocytosis Activity in Central Obesity

Background Obesity is expected to hinder efferocytosis due to ADAM17-mediated cleavage of the MER tyrosine kinase receptor, producing soluble MER (sMER) that disrupts MERTK binding to cell death markers. However, the intracellular efferocytosis pathway in central obesity remains elusive, particularly the role of low-grade chronic inflammation in its initiation and identification of binding signals that disrupt efferocytosis. Objective We investigate the efferocytosis signaling pathway in men with central obesity and its relationship with inflammation, cell death, and related processes. Methods A cross-sectional study was conducted, and clinical data and blood samples were collected from 56 men with central obesity (obese group) and 29 nonobese individuals (control group). Clinical evaluations and predefined biochemical screening tests were performed. The efferocytosis signaling pathway was investigated by measuring phosphatidylserine (PS), ADAM17, TNF-alpha (TNF-α), and sMER. Results Metabolic syndrome was detected in more than half of the participants in the obese group according to the predefined tests. Mean levels of PS, TNF-α, and sMER were higher in the obese group but not significantly different from those of the control group. Further analysis based on waist circumference (WC) ranges in the obese group revealed a significant increase in PS and sMER levels between the control group and the obese group with WC greater than 120 cm. ADAM17 levels were significantly higher in the obese group than in the control group. PS was positively correlated with WC and ADAM17. ADAM17 was positively correlated with TNF-α and sMER, indicating impaired efferocytosis. Conclusions Central obesity appeared to cause a disturbance in efferocytosis that began with cell damage and death, along with an enlargement of the WC and an ongoing inflammatory response. Efferocytosis was disrupted by proinflammatory cytokine regulators, which induced the production of sMER and interfered with the efferocytosis process.


Introduction
Obesity has become a global epidemic in the past decade and has grown rapidly in developing countries, including Indonesia [1].To put it simply, obesity is primarily caused by excessive calorie intake.Fat accumulation in the visceral area is known to lead to metabolic abnormalities, referred to as "central obesity" by the World Health Organization (WHO) for the Asia-Pacifc region, and is defned as a waist circumference (WC) greater than 90 cm in males [2,3].
During central obesity, hypertrophy of the adipose tissue triggers the unbalanced secretion of adipokines and increases the production of free fatty acids, leading to metabolic syndrome and modulates infammatory reactions, glucose, and lipid metabolism [4].Increased cell death during central obesity leads to increased macrophage infltration, which creates a crown-like structure (CLS) that surrounds the dead adipocytes [5].Tumor necrosis factor alpha (TNF-α) cytokines are mainly produced by adipose tissue macrophages, which are proinfammatory [6].TNF-α converting enzyme, also known as a disintegrin and metalloproteinase 17 (ADAM17), regulates the expression of these cytokines [7] and is activated by the transfer of phosphatidylserine (PS) to the outer membrane of adipocytes during cell injury and death [8].Te increased efect of ADAM17 in central obesity is related to a decrease in the expression of the tissue inhibitor metalloproteinase 3 (TIMP3) [9].
Adipocyte cell death is apoptotic and is removed by phagocytes, particularly macrophages, as part of the cell remodeling process.Rapid and efcient clearance of apoptotic cells by macrophages is critical to maintain tissue homeostasis and prevent secondary necrosis, which increases infammation [10,11].Tis process of clearing apoptotic cells is called eferocytosis.Te eferocytosis process is divided into three stages: recognition, binding, and cell death degradation [12,13].Various markers of each stage have been identifed.However, these identifed markers are limited to in vivo testing.One of these markers is the MER proto-oncogene tyrosine kinase (MERTK) receptor, which plays a pivotal role in the binding process.Tis receptor is located on the surface of macrophages and binds to bridge molecules produced by apoptotic cells, such as protein S and growth arrest-specifc protein 6 (Gas6), which have a high afnity for PS [14,15].Eferocytosis impairment is predicted due to interference with the MERTK receptor.Te research by Suresh Babu et al. showed that eferocytosis was altered in macrophages of obese and diabetic mice [16].Tis impairment was caused by the shedding of MERTK by ADAM17, which functions as the main protease [16].Te proteolytic cleavage of MERTK produced soluble MERTK (sMER) [17], which interacts with Gas6 and protein S, thus disrupting its binding with the MERTK receptor on macrophage membranes.Tis decreases the intracellular downstream signaling that modulates eferocytosis and the resolution of infammation [16,18].However, further research is needed to investigate this intracellular eferocytosis pathway in humans with central obesity.
By recognizing the global urgency of understanding obesity-related processes, our study emphasizes the importance of noninvasive methods, such as blood tests, for ethical and scalable research.Tis method helps us study a larger group of people, ensuring more reliable fndings.In this study, our aim was to understand eferocytosis signaling in central obesity, especially how low-grade chronic infammation triggers the process and to identify binding signals that activate eferocytosis.Markers important in obesity and eferocytosis (e.g., PS, ADAM17, TNF-α, and sMER) were observed between the obese and nonobese groups, opening the opportunity to identify potential biomarkers for therapeutic exploration.

Materials and Methods
2.1.Participants.Tis was a cross-sectional study aimed to investigate the impact of central obesity on eferocytosis signaling in visceral adipose tissue.A total of 103 male participants were randomly selected to participate in this study, with recruitment conducted from January to August 2022.Participants were initially divided into two groups based on a predefned criteria for further analysis, with 56 participants with central obesity (obese group) and 29 nonobese individuals (control group).However, 18 participants were excluded from the study due to various reasons, including acute infammation, impaired liver function, and a history of carcinoma.Te initial division into the two groups aimed at exploring the potential diferences between the control and overall obese groups.To further investigate potential variations in specifc eferocytosis markers (PS, ADAM17, TNF-α, and sMER) within the obese population, the obese group was subsequently subdivided based on WC range into three subgroups (the level of obesity): obese 1 group (WC: 91-110 cm), obese 2 group (WC: 110-120 cm), and obese 3 group (WC > 120 cm).
Obesity was diagnosed according to WHO criteria for the Asia-Pacifc region, which defnes obesity as a body mass index (BMI) of ≥25 kg/m 2 and central obesity as a WC ≥ 90 cm [3].Te number of participants in this study was calculated by using the formula for the quantitative variable with [19] n where n is the number of samples, P is the proportion of subjects in the study at 0.5 with a confdence interval of 95%, Z 1−α/2 is the expected signifcance at 1.96, ε is the estimated prevalence of obesity in Indonesia at around 21.8% based on the 2018 Indonesia Basic Health Research [20], and n is the minimum sample size of 81 subjects.Participants in this study were men 30-50 years old, with normal liver functions, and no evidence of acute infection, a history of autoimmune disorders, or malignancies during examination.Te presence of autoimmune disorders or cancer among the participants was assessed using a questionnaire to ensure the validity of the study.High-sensitivity C-reactive protein (hs-CRP) levels were measured using chemiluminescent method assay kits (Siemens, USA), which were centrifuged at 3000 rpm for 15 min prior to analysis.Te level of hs-CRP was used to diferentiate between participants with acute infection (hs-CRP >10 mg/L) and those without (hs-CRP <10 mg/L) [22].Te study excluded participants with acute infections to ensure that hs-CRP levels accurately refected chronic infammatory status.

Ethical
Te metabolic syndrome was identifed using international criteria, including dyslipidemia and hyperglycemia.Te diagnostic criteria for metabolic syndrome in men were based on the NCEP ATP III and the American Heart Association guidelines and included WC greater than 40 inches (>102 cm), BP greater than 130/85 mmHg, fasting triglyceride (TG) level >150 mg/dL, fasting HDL <40 mg/dL, and fasting blood sugar >100 mg/dL [23].Te American Diabetes Association recommends the use of HbA1c as an indicator of the risk of diabetes, as it has a less variability daily and is less afected by disease and stress.Te HbA1c test was used to diagnose type 2 diabetes mellitus (T2DM) using HPLC, which is certifed by the National Glycohemoglobin Standardization Program.Te samples used were whole blood, and the HbA1c concentration was analyzed using HbA1c assay kits (Variant Turbo, Bio-Rad, USA) according to the manufacturer's instructions.Te cholesterol profle was measured using an enzymatic colorimetric method in ARCHITECT c4000 (Abbott, USA), which included total cholesterol, low-density lipoprotein cholesterol (LDL cholesterol), high-density lipoprotein cholesterol (HDL cholesterol), and TG, to determine the presence of dyslipidemia.Dyslipidemia is diagnosed when one of the serum lipids is outside the normal reference range, where non-HDL cholesterol � total cholesterol − HDL cholesterol.

Statistical Analysis.
Te results were presented as the mean ± standard error of mean (SEM) of the replicate assays, and the normality of the data was assessed prior to selecting the parametric tests.Te Kolmogorov-Smirnov method was used to determine the distribution of the data (normal/ abnormal) between all groups.Te Mann-Whitney method was used to compare the two groups, and the correlation between two quantitative parameters was evaluated using the Spearman correlation coefcient.IBM SPSS version 23.0 statistical software (IBM, USA) was utilized for all statistical analyses and graph creation.An acceptable 5% error margin was established, and the confdence interval was established at 95%.Terefore, a p value of <0.05 was considered signifcant.

Characteristics of the Participant.
A total of 103 male participants aged 30-50 years were randomly selected to participate in this study.Participants were divided into two groups, the obese group and the nonobese (control) group, according to eligibility requirements for BMI and WC.Eighteen participants were excluded from the study.Twelve were excluded from the obese group due to acute infammation, while six participants showed potentially impaired liver function (5 in the obese group and 1 in the control group).Furthermore, a participant in the obese group had a history of hepatocellular carcinoma.Finally, 85 individuals were retained for further analysis, with 56 participants in the obese group and 29 in the control group.
Te demographic and metabolic characteristics of the participants are presented in Table 1.BMI and WC were signifcantly higher in the obese group (p < 0.001), with values of 34.1 ± 0.6 kg/m 2 and 115.9 ± 1.2 cm than 22.7 ± 0.4 kg/m 2 and 84.1 ± 0.9 cm in the control group, respectively.Tese results confrmed that the participants were selected according to the study inclusion criteria.Tere was no age diference between the groups (39.3 ± 0.7 vs. 38.5 ± 0.9 years in the obese and control groups, respectively).Data showed that higher BMI and WC were associated with higher rates of comorbidity.Mean levels of serum SGOT and SGPT were signifcantly higher in the obese group than in the control group (p < 0.05), while the SGOT : SGPT ratio was unremarkable (<1).Furthermore, the obese group had a signifcantly higher prevalence of diabetes (25% vs. 0%) and prediabetes (35% vs. 7%) than the control group, respectively, with a mean HbA1c value of 6.2% ± 0.2% compared to 5.3% ± 0.6% in the control group (p < 0.001).In terms of the classifcation of cardiovascular Journal of Obesity risk based on hs-CRP level [24], half of the participants in the obese group had a level of >3.0 mg/L, indicating a higher cardiovascular risk compared to only 14% in the control group.hs-CRP levels in the obese and control groups were statistically diferent (p < 0.001), with values of 5.2 ± 0.4 and 1.6 ± 0.4 mg/L, respectively.We found that 98% and 52% of participants in the obese and control groups, respectively, had dyslipidemia.Serum lipid levels, including LDL cholesterol, HDL cholesterol, and TG, were signifcantly different in the obese group compared to the control group (p < 0.05).Furthermore, we found that 67% of participants in the obese group and 7% in the control group had hypertension.Systolic and diastolic BP levels in the obese group were signifcantly higher than those in the control group (p < 0.001), with values of 140.6 ± 2.2 vs. 124.2± 2.2 mmHg and 94.5 ± 1.5 vs. 79.9 ± 1.6 mmHg, respectively.
Based on the classifcation of metabolic syndrome, 41 of 65 obesity participants (63%) met the criteria for metabolic syndrome, while no participants in the control group had metabolic syndrome.Tese results suggest an association between obesity and various metabolic and cardiovascular risk factors.

Correlation of WC with Metabolic Syndrome.
In this study, the correlation between WC and components of metabolic syndrome was explored, including BMI, SGOT, SGPT, HbA1c, hs-CRP, and cholesterol profles.As presented in Table 2, a signifcant positive association was observed between WC and BMI (p < 0.001).Given this fnding, we considered the subsequent correlations with the WC levels.WC was found to be signifcantly positively correlated with SGOT and SGPT (p < 0.05) and the relationship of WC with HbA1c and hs-CRP also showed a strong positive correlation (p < 0.001), indicating that increased WC may be a marker of poor glycemic control and chronic infammation.A strong positive correlation was observed between WC and LDL cholesterol, TG, and non-HDL cholesterol (p < 0.05).In particular, a robust negative correlation was found between WC and HDL cholesterol (p < 0.001).Furthermore, WC exhibited a signifcant positive correlation with BP levels (p < 0.001), implying that individuals with a larger WC may have a greater risk of hypertension.

Eferocytosis in the Obese and Control Groups.
Te eferocytosis process in this study was observed by measuring the levels of PS, ADAM17, TNF-α, and sMER as shown in Table 3. Te mean level of PS in the obese group was higher than that in the control group; however, this diference was not statistically signifcant.Similarly, mean levels of TNF-α and sMER were higher in the obese group than in the control group, although the diference was not statistically signifcant.Interestingly, the fndings revealed that the ADAM17 level was signifcantly higher in the obese group than in the control group (p < 0.001).
Based on these observations, we proceeded to examine the levels of PS, ADAM17, TNF-α, and sMER based on the WC ranges.As presented in Table 4, PS levels difer signifcantly between the control group and the obese group 3 (p < 0.05), but no signifcant diferences were observed between the control group and obese groups 1 and 2. Furthermore, there is a signifcant diference in PS levels between obese groups 2 and 3 (p < 0.05).Table 4 further illustrates that the mean PS levels in obese group 1 are lower than those in the control group.Furthermore, signifcant diferences in sMER levels are evident between the control group and the obese group 3 (p < 0.05), as well as between  4 Journal of Obesity the obese groups 2 and 3 (p < 0.05).Interestingly, a similar decrease pattern is observed for sMER levels in groups 1 and 2, which have lower levels than the control group.Regarding ADAM17 levels, signifcant diferences are observed from the control group to the obese group 1 (p < 0.05) and similarly between the control group and the obese groups 2 and 3.However, TNF-α levels show no signifcant diferences between the control group and obese groups 1, 2, and 3 (p > 0.05).In Table 4, it is evident that PS, ADAM17, and sMER levels difer signifcantly between the control group and the obese group 3 that had WC > 120 cm.

Discussion
Obesity has been shown to trigger cellular apoptosis and infammation in adipose tissue, exacerbating the risk of various detrimental health outcomes, including but not limited to T2DM, dyslipidemia, hypertension, and hepatic steatosis.Collectively, these conditions constitute a syndrome referred to as "metabolic syndrome" [25,26].Intriguingly, our study revealed that more than 50% of participants with obesity were unaware of their status of metabolic syndrome.Tis fnding validates previous investigations that reported a positive association between increased visceral adiposity and increased symptoms of metabolic syndrome symptoms [27,28].
Adipose tissue is a major source of infammatory markers in obesity.During the infammatory process, visceral adipose tissue also produces proinfammatory cytokines and contributes to an increase in serum hs-CRP levels by increasing its signaling [29,30].Previous studies have revealed a strong positive association between obesity measurements, such as WC and hs-CRP [31].Our research also found a strong positive correlation between WC and hs-CRP levels (p < 0.001).Hs-CRP is made by the liver in response to infammatory cytokines such as TNF-α.Unfortunately, a signifcant correlation between hs-CRP and TNF-α was not detected in this study.According to Table 3, there were no statistically signifcant diferences in the TNFα levels between the obese and control groups.Although there was an increasing trend in the mean value of the obese group, the average value remained relatively constant.Te lack of a signifcant correlation between hs-CRP and TNF-α in this research could be due to several factors.One possibility is that the history of other infections such as COVID-19 could infuence this result, particularly in the control group, where 59% of the participants had previously been infected with COVID (compared to 48% in the obese group) and had been disease-free for at least three months before participating in this research.TNF-α levels were signifcantly higher in patients with postacute COVID-19 than in those with no prior exposure to COVID-19, according to a German cohort study that recruited post-COVID-19 patients [32].Elevated levels of TNF-α remained stable in individuals with ongoing postacute COVID-19 sequelae who experienced prolonged symptoms until 10 months after COVID-19 testing [32].Even though the hs-CRP value was established at <10 mg/L to demonstrate that there was no acute infection, it appears that cellular infammation occurs post-COVID-19.However, as a chronic infammatory marker, hs-CRP in the obese group difered signifcantly from the control group (p < 0.001), which indicates a higher chronic infammation in the obese group.Another possibility is that other infammatory markers or signaling pathways may promote the observed association between obesity and hs-CRP levels, independently of TNF-α.For example, adipose tissue can produce a variety of other proinfammatory cytokines, such as IL-6, that can contribute to the observed increase in hs-CRP levels in obese individuals.Other studies have suggested that factors such as oxidative stress and insulin resistance may play a role in the link between obesity and infammation [33].
Infammation, metabolic processes, and cell death are highly interrelated processes in obesity.One of the most obvious signs of cell death is the movement of PS from the inside to the outside of the leafet of the cell plasma membrane.A previous study by Solá et al. [34] compared the expression of PS in obese patients and a control group and it was reported that obese patients had a signifcantly higher PS expression than the control group.However, another previous study by Samocha-Bonet et al. did not fnd any difference in the expression of PS between the two groups, although the expression of PS showed an increasing trend in  6

Journal of Obesity
Journal of Obesity the obese group [35].In our study, we found that the mean level of PS was higher in the obese group than in the control group, and this increase was correlated with the increase in WC (p < 0.05).Te discrepancy between the results of this study and Solá et al. does not appear to be related to the sample size (49 cases); however, it could be related to the diferent degrees of obesity, since the mean BMI levels and WC in the study by Sola et al. were 46.1 ± 6.5 kg/m 2 and 127 ± 15 cm, respectively [34].Te further analysis we performed is similar to the study by Solá et al. [34], which indicates that in the obese group with WC greater than 120 cm in this study, the levels of PS are signifcantly different from those in the control group.Based on these fndings, the degree of obesity appears to contribute to the elevation of PS levels.Externalization of PS has traditionally been considered as an "eat-me" signal for apoptotic cells, where PS is transferred to the outer leafet of the cell membrane, leading to ADAM17 activation [36,37].In this study, a signifcant positive correlation was observed between PS and ADAM17 levels (p < 0.05).Although no statistically signifcant differences were found in PS levels between the obese and control groups, our fndings indicated higher PS levels in the obese group than in the control group.Furthermore, PS levels were higher in the obese group with WC greater than 120 cm than in the control group.In this study, ADAM17 levels difered signifcantly between the obese and control groups, even between the control group and the obese group with a WC of 91-110 cm.In addition to PS, other factors involved in ADAM17 regulation in obesity should also be considered, as previous research has shown that obesity is characterized by a defciency of TIMP3 in white adipose tissue and liver, resulting in elevated ADAM17 levels [38,39].Furthermore, alterations in ERK or p38 MAPK signaling pathways have been shown to afect the dynamic balance between the conformations of ADAM17 dimers and monomers [38].
ADAM17 plays a crucial role in the proteolytic release of proinfammatory cytokines from cellular membranes, with TNF-α being a major cytokine processed by ADAM17, produced by various cell types and contributes to infammation [7].Tis study revealed a strong positive correlation between ADAM17 and TNF-α (p < 0.05).Furthermore, this study revealed a signifcant disparity in ADAM17 levels between the obese and control groups, suggesting that ADAM17 plays a multifaceted role beyond its involvement in the production of proinfammatory cytokines.Previous studies have shown that ADAM17 regulates more than 90 substrates that are involved in various cellular processes, including infammation signaling, immune response, phagocyte infltration, and cell development [40,41].
Our fndings also revealed a strong positive correlation (p < 0.001) between PS and TNF-α levels, which is consistent with the established correlations between PS and ADAM17, and ADAM17 and TNF-α.Tis suggests that the regulation of TNF-α may be infuenced by PS through its association with ADAM17.Although TNF-α levels did not show a statistically signifcant diference between the obese and control groups, a signifcant diference was observed in ADAM17 levels between the two groups (p < 0.001).Unfortunately, we did not measure other cytokines that are regulated by ADAM17, such as IL-6 and CX3CL-1, preventing a comparison of their levels with TNF-α.We acknowledge that the measurement of markers in obesity may depend on the degree of obesity that can infuence cellular processes at diferent stages, which could potentially explain the lack of signifcant diferences in markers such as TNF-α and PS, as ongoing cellular repair processes may be occurring.We also suggest that at a certain degree of obesity, especially the mechanism of hyperplasia plays a signifcant role in compensating for the hypertrophic efect, which results in a potential anti-infammatory efect that mitigates the proinfammatory consequences.Tis suggests that cellular processes in obesity are complex and multifaceted, with a delicate balance between proinfammatory and antiinfammatory efects.
In obesity, adipose cell hypertrophy is a possible risk factor for cellular damage and death [42].To comprehend the process that leads to cell death, we examined its correlation with infammatory markers such as TNF-α and its regulator, ADAM17.As part of the cell remodeling process, macrophages play a vital role in maintaining tissue homeostasis by engaging in eferocytosis and preventing Journal of Obesity secondary necrosis [36].When macrophages infltrate adipose tissue, they arrange themselves around dead cells and form a CLS to engulf and eliminate the dead cells [43].Moreover, the CLS also secretes proinfammatory factors such as TNF-α [44].During eferocytosis, the macrophage MERTK functions as crucial receptors in the binding process [14], and in this study, we focused on measuring sMER levels.Although there were no statistically signifcant differences in sMER levels between the obese and control groups, the mean level of sMER in the obese group was higher than that in the control group.Tis fnding difers from that of Suresh Babu et al. [16], who reported that in vitro eferocytosis was impaired in macrophages from obese and diabetic mice due to increased levels of sMER, leading to a decline in MERTK function.In addition, in this study, it was revealed that sMER levels were signifcantly diferent between the control group and the obese group with a WC greater than 120 cm.Interestingly, our study suggests that the degree of obesity appears to regulate changes in sMER levels, similar to what we observed with PS levels.However, our study revealed a positive correlation between sMER and ADAM17 (p < 0.05).Te positive correlation between sMER and ADAM17 is consistent with the fndings of Babu et al., who reported that disruption of eferocytosis occurs through the release of MERTK by ADAM17, which acts as the main protease, and produces sMER [16].However, research on sMER in humans using serum samples remains limited, and more studies with larger sample sizes are required to confrm these fndings.To further explore the correlation between sMER  .Phagocytic cells, primarily macrophages, recognize PS as a "fnd me" signal.Meanwhile, protein S/Gas6 acts as an "eat-me" signal, binding to MERTK on phagocytic cells to initiate the clearance of damaged or dead cells and their components.PS, once bound to its receptor in phagocytic cells, activates ADAM17, which cleaves various cytokines such as TNF-α, serving as an infammation marker.Tis leads to an increase in circulating TNF-α.However, ADAM17 also cleaves MERTK in phagocytic cells, generating sMER in the circulation.When sMER is high, it interferes with eferocytosis because it binds to the protein S/Gas6, which is made by damaged or dead cells.Consequently, competition arises between MERTK and sMER, which interferes with the eferocytosis process. 8 Journal of Obesity and cellular function, additional research is needed to compare sMER levels obtained through in vitro and serum samples.Such a study would be valuable, since sMER circulates in the bloodstream and investigating its correlation with cellular function could provide insight into the mechanisms underlying the potential risk of cellular damage and death in central obesity.
Based on the results and the correlation between the parameters mentioned above, we illustrate the eferocytosis process in central obesity in Figure 1.

Conclusions
Our research investigated the relationship between obesity and infammatory markers, cell death, metabolic syndrome, and eferocytosis.Identifed markers may be valuable in the development of efective therapies.Te results demonstrated that central obesity triggered infammation and cell death in adipose tissue, increasing the risk of metabolic syndrome.Impaired clearance of dead cells and debris in central obesity led to their accumulation, which activated immune cells and induced cytokine regulators such as ADAM17 to increase the infammatory milieu.Tis cycle of cell death, impaired clearance, and infammation further disrupted eferocytosis with increased levels of sMER.Tus, we conclude that PS, ADAM17, and sMER play an important role in eferocytosis activity in central obesity.More research is required to fully elucidate the intricate relationship between obesity, infammation, cellular death cells, eferocytosis, and metabolic processes to develop improved preventive and treatment therapy.

Figure 1 :
Figure1: Illustrating the mechanism of eferocytosis impairment in central obesity.Te cellular mechanism in central obesity continually leads to the damage and death of adipocytes.Tis is shown by the movement of PS to the outside of the cell membrane and the release of protein S/Gas6 and extracellular vesicles (EVs).Phagocytic cells, primarily macrophages, recognize PS as a "fnd me" signal.Meanwhile, protein S/Gas6 acts as an "eat-me" signal, binding to MERTK on phagocytic cells to initiate the clearance of damaged or dead cells and their components.PS, once bound to its receptor in phagocytic cells, activates ADAM17, which cleaves various cytokines such as TNF-α, serving as an infammation marker.Tis leads to an increase in circulating TNF-α.However, ADAM17 also cleaves MERTK in phagocytic cells, generating sMER in the circulation.When sMER is high, it interferes with eferocytosis because it binds to the protein S/Gas6, which is made by damaged or dead cells.Consequently, competition arises between MERTK and sMER, which interferes with the eferocytosis process.

Table 2 :
Correlation of WC with routine biomarker results and BP levels in the study group.

Table 1 :
Clinical characteristics of the participants.
e comparison of confdence interval between the obese 2 and obese 3 groups.* Signifcant in the 95% confdence interval (p < 0.05) using the Mann-Whitney test.

Table 5 :
Correlation between each parameter in the study group.Signifcant in the 95% confdence interval using the Spearman correlation test.