Increased circulatory levels of fractalkine (CX3CL1) are associated with inflammatory chemokines and cytokines in individuals with type-2 diabetes
© The Author(s). 2017
Received: 23 January 2017
Accepted: 26 March 2017
Published: 4 April 2017
Fractalkine (CX3CL1) is involved in the development of numerous inflammatory conditions including metabolic diseases. However, changes in the circulatory fractalkine levels in type-2 diabetes (T2D) and their relationship with inflammatory chemokines/cytokines remain unclear. The aim of the study was to determine the T2D-associated modulations in plasma fractalkine levels and investigate their relationship with circulatory chemokines/cytokines.
A total of 47 plasma samples were collected from 23 T2D and 24 non-diabetic individuals selected over a wide range of body mass index (BMI). Clinical metabolic parameters were determined using standard commercial kits. Fractalkine and chemokines/cytokines were measured using Luminex X-MAP® technology. C-reactive protein (CRP) was measured by ELISA. The data were compared using unpaired t-test and the dependence between two variables was assessed by Pearson’s correlation coefficient (r).
Plasma fractalkine levels were significantly higher (P = 0.005) in T2D patients (166 ± 14.22 pg/ml) as compared with non-diabetics (118 ± 8.90 pg/ml). In T2D patients, plasma fractalkine levels correlated positively (P ≤ 0.05) with inflammatory chemokines/cytokines including CCL3 (r = 0.52), CCL4 (r = 0.85), CCL11 (r = 0.51), CXCL1 (r = 0.67), G-CSF (r = 0.91), IFN-α2 (r = 0.97), IL-17A (r = 0.79), IL-1β (r = 0.97), IL-12P70 (r = 0.90), TNF-α (r = 0.58), and IL-6 (r = 0.60). In non-diabetic individuals, fractalkine levels correlated (P ≤ 0.05) with those of CCL4 (r = 0.49), IL-1β (r = 0.73), IL-12P70 (r = 0.41), and TNF-α (r = 0.50). Notably, plasma fractalkine levels in T2D patients associated with systemic inflammation (CRP) (r = 0.65, P = 0.02).
The altered plasma fractalkine levels associate differentially with inflammatory chemokines/cytokines in T2D patients which may have implications for T2D immunopathogenesis.
KeywordsFractalkine CX3CL1 Chemokines Cytokines Inflammation Obesity Type-2 diabetes
The chronic low-grade systemic inflammation associated with obesity called as metabolic inflammation is a contributory factor to the induction of insulin resistance and development of type-2 diabetes (T2D) and also leads to other clinical complications of metabolic syndrome [1, 2]. Altered circulatory levels of various chemokines, proinflammatory cytokines, and adipokines have been widely reported both in obesity and T2D [3–5]. The proinflammatory cytokines and chemokines are involved in the pathogenesis of a wide variety of inflammatory disorders. Macrophage inflammatory proteins (MIP) belong to CC-motif chemokines and the two isoforms called MIP-1α (CCL3) and MIP-1β (CCL4) are induced by exposure of macrophages to endotoxins and the elevated expression of these inflammatory proteins was observed in primary monocytes obtained from T2D patients . Similarly, the increased circulatory levels of CXC-motif chemokines were reported in patients with type-1 diabetes [7, 8]. The elevated circulatory levels of CXCL1 and CXCL5 in T2D patients  and the increased CCL11 (Eotaxin) protein in serum and mRNA in visceral adipose tissue of obese mice and humans have been reported ; and these chemokines may affect the recruitment of eosinophils, basophils, neutrophils, and monocytes at the site(s) of inflammation. These immune regulatory cells synthesize and release proinflammatory cytokines such as IL-1, IL-6, and TNF-α which are regarded as the key factors involved in metabolic dysregulation including glucose and lipid disorders and insulin resistance in T2D [11–13]. The T-helper (Th)-17 cells express proinflammatory cytokine IL-17 which regulates adipogenesis, glucose homeostasis and obesity ; and it has been also implicated in the pathogenesis of several inflammatory diseases including rheumatoid arthritis, psoriasis, systemic sclerosis, and T2D [15–18].
Fractalkine, also known as CX3CL1, is a chemokine with chemotactic activity for monocytes, T cells, and NK cells, all of which play important roles in the development of numerous inflammatory conditions including arthritis, atherosclerosis, insulin resistance and T2D [19–21]. However, it is not clear whether the plasma fractalkine levels are modulated in T2D, and if so, how do these changes relate with the inflammatory chemokines and cytokines in diabetic patients. Therefore, the aim of the study was to determine the circulatory fractalkine levels in T2D and non-diabetic individuals and to also find the relationship between plasma fractalkine and inflammatory chemokines/cytokines in these subjects. Herein, we present the data showing significantly higher plasma fractalkine levels in T2D patients as compared with non-diabetic controls. Furthermore, these changes correlated positively with signature inflammatory chemokines and cytokines in the circulation.
Patients’ demographic characteristics and clinical data
Total number (N)
48.5 ± 3.7
48.0 ± 2.8
51.3 ± 5.9
38.5 ± 4.4
42.6 ± 3.7
40.5 ± 4.5
Body mass index (Kg/m2)
23.4 ± 0.6
27.3 ± 0.5
33.1 ± 0.7
22.6 ± 0.7
27.4 ± 0.7
35.9 ± 1.6
Body fat (%)
30.0 ± 3.1
31.4 ± 2.7
34.9 ± 1.4
29.7 ± 1.8
35.1 ± 1.3
41.9 ± 1.4
Waist circumference (Cm)
76.4 ± 3.0
90.0 ± 5.5
113.4 ± 1.6
78.2 ± 3.2
94.5 ± 3.4
110.1 ± 2.3
Waist to hip ratio
0.82 ± 0.05
0.90 ± 0.03
0.96 ± 0.04
0.81 ± 0.03
0.95 ± 0.01
0.97 ± 0.02
Fasting plasma glucose (mmol/L)
8.0 ± 1.1
7.4 ± 0.7
9.2 ± 1.1
4.9 ± 0.1
5.3 ± 0.2
5.7 ± 0.3
Glycated hemoglobin (HbA1c) (%)
7.5 ± 0.8
6.8 ± 0.5
9.2 ± 0.7
5.4 ± 0.3
5.7 ± 0.1
5.4 ± 0.2
Total cholesterol (mmol/L)
5.6 ± 0.4
5.0 ± 0.5
5.6 ± 0.7
5.1 ± 0.3
5.5 ± 0.3
5.0 ± 0.3
High-density lipoprotein (mmol/L)
1.5 ± 0.4
1.2 ± 0.1
1.1 ± 0.2
1.5 ± 0.2
1.4 ± 0.1
1.4 ± 0.1
Low-density lipoprotein (mmol/L)
3.5 ± 0.2
3.2 ± 0.5
3.4 ± 0.6
3.1 ± 0.2
3.5 ± 0.3
3.0 ± 0.2
1.5 ± 0.3
1.4 ± 0.3
2.1 ± 0.8
0.7 ± 0.1
1.2 ± 0.2
1.2 ± 0.2
Determination of plasma chemokines/cytokines
A total of 41 chemokines and cytokines were measured using panel MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel-Premixed 41 Plex-Immunology Multiplex Assay (Milliplex map kit, HCYTMAG-60 K-PX41; Millipore, USA) following the manufacturer’s instructions. Data from the reactions were acquired using Luminex, Milliplex analyzer while a digital processor managed the data output and Milliplex analyst software was used to determine the mean fluorescence intensity (MFI) and analyte concentration (pg/mL).
The data obtained were expressed as mean ± SEM values and group means were compared using unpaired t-test. The linear dependence between two variables was assessed by Pearson’s correlation coefficient (r). GraphPad Prism software (Version 6.05; San Diego, CA, USA) was used for statistical analysis as well as for graphical representation of the data. All P-values ≤0.05 were considered as statistical significant.
Increased fractalkine levels in diabetic individuals
Fractalkine in diabetic individuals associates with most of inflammatory chemokines
Fractalkine in diabetic/non-diabetic individuals associates with inflammatory cytokines
The increasing evidence supports that proinflammatory chemokines/cytokines are important players in establishing the conditions required for insulin resistance, T2D, and other related complications [2, 22–24]. As a chemoattractant and an adhesion factor, fractalkine orchestrates the inflammatory cell recruitment and colonization at sites of inflammation, such as expanding white adipose tissue in obesity and T2D. Fractalkine has been reported to be involved in monocyte adhesion to adipocytes and its expression by human adipocytes and stromal vascular cells was found to be associated with obesity, insulin resistance, and T2D . In the present study, we report significantly higher plasma fractalkine levels in T2D patients as compared with non-diabetic individuals. In agreement with this finding, at least in part, Shah et al. also showed that plasma fractalkine levels were associated with adipose and metabolic traits and its levels were higher in T2D patients as compared with non-diabetic controls . However, we did not find a significant difference of fractalkine levels between obese and control subjects which may be due to small numbers of subjects in each group. Also, it is not clear whether the obesity was a significant player in upregulating fractalkine expression in our diabetic patients but a human study of allergic asthma found that obesity was associated with enhanced fractalkine levels and leukocytic infiltration . Although, the definitive cause(s) of higher fractalkine levels in patients with metabolic disease currently remain unclear, a link with obesity/T2D associated inflammation was reported [25, 27]. Both CX3CL1 mRNA and protein expression was found to be elevated in obese as compared with lean adipose tissue .
Our data further show that the elevated fractalkine expression in T2D patients correlates positively with the expression of other inflammatory chemokines such as CCL3, CCL4, CCL11 and CXCL1. The changes in plasma chemokines’ levels have been reported earlier in obesity and T2D . CCL3 and CCL4 are the major chemotactic proteins produced by macrophages and adipose tissue. The positive association between fractalkine and these chemokines indicates that fractalkine, as a key regulator of leukocyte infiltration and adhesion, may be involved in the cross regulation of other chemokines. CCL11 or eotaxin-1 is predominantly an eosinophil chemotactic factor which is known to bind with CCR2, CCR3, and CCR5 chemokine receptors [29, 30]. CCL11, which is a chemoattractant for eosinophils, basophils, neutrophils, and monocytes, can play a significant role in the regulation of many inflammatory conditions including metabolic diseases. Notably, increased adipose tissue levels of multiple β-chemokines (CCL2, CCL3, CCL5, CCL7, CCL8, CCL11) and chemokine receptors (CCR1, CCR2, CCR3, CCR5) have been linked with obesity and associated metabolic inflammation . CXCL1 or Gro-α which is expressed by macrophages, neutrophils, and epithelial cells, displays neutrophil chemoattractant activity and is a key regulator of hepatic neutrophil infiltration . CXCL1 and CXCL5 were found to be elevated in the circulation with the onset of T2D and these chemokines were suggested to participate in the pathogenesis of T2D . The patients with type-1 diabetes (T1D) or T2D were found to have elevated serum levels of CXCL1 as compared with non-diabetic controls [7, 8, 33].
We also found that fractalkine expression correlated positively with the circulatory levels of G-CSF, IFN-α2, IL-17A, and IL-6 only in diabetic subjects while it was found to be associated with IL-1β, IL-12p70, and TNF-α in both diabetic and non-diabetic individuals. These data suggest that fractalkine has a broader relationship with important proinflammatory cytokines and it may also have a differential association with these inflammatory proteins in the presence or absence of T2D. Our data indicate that the positive association of fractalkine with IL-1β, IL-12p70, and TNF-α may, therefore, be more consistent than its relationship with other proinflammatory cytokines including G-CSF, IFN-α2, IL-17A, and IL-6 as these cytokines were detected exclusively in T2D patients. TNF-α and IL-6 are considered the major players in chronic low-grade inflammation and insulin resistance. In partial agreement with our results, elevated levels of these proinflammatory cytokines were also reported in T2D patients by another study . Chemokines, through activation of leukocytes, may lead to the induction of several proinflammatory cytokines including IL-1β, TNF-α, and IL-6. IL-17A is a proinflammatory cytokine which may be upregulated by fractalkine in T2D patients indirectly by the enhanced T cell infiltration and/or directly by the activation of Th17 cells in the adipose tissue. IL-17 stimulates the production of IL-6 in differentiated adipocytes and the enhanced IL-6 expression may in turn favor the proinflammatory Th17 subset differentiation . In T2D patients, T cells are naturally skewed toward proinflammatory phenotypes (Th17 and Th1) that likely play a role to induce chronic sub-acute inflammation in T2D patients through the upregulated inflammatory cytokine production. In addition to IL-6, IL-1β and TGF-β can also induce Th17 differentiation in T2D patients [36, 37]. G-CSF is a cytokine and a hormone that acts as a colony stimulating factor for granulocytes and stem cells, as well as it also promotes the proliferation and differentiation of neutrophils. Our data showing the elevated levels of G-CSF in T2D patients may have significant implication as a recent study also indicated that G-CSF could be a major player in free fatty acid (FFA)-induced insulin resistance since the treatment with G-CSF led to insulin resistance in human adipocytes and myotubes . Our data also show increased levels of IFN-α2 in T2D pateints which is a type-I interferon and it may be induced in these patients in the presence of danger signals from the dead or dying cells, such as during lipolysis observed in morbid obesity and T2D. Consistent with our data showing increased IL-12 levels in the peripheral circulation of both T2D and non-diabetic individuals, Suarez-Alvarez et al. also found elevated serum IL-12 levels in overweight and adult obese individuals and this IL-12 induction was found to strongly correlate with markers of low-grade inflammation and obesity . IL-12 plays a role in the differentiation of naïve T cell into proinflammatory Th1 cells, it stimulates the production of IFN-γ and TNF-α, and also plays a critical role in the activation of T cells and NK cells . We further found that in T2D patients, plasma fractalkine levels were associated with circulatory concentrations of CRP which is a signature clinical marker for systemic inflammation. These results are in agreement with other studies that also report the increased CRP levels in obese/T2D individuals [41, 42].
Fractalkine is the only member of CX3C chemokine family which is constitutively expressed by several hematopoietic and non-hematopoietic cells. The biological effects of fractalkine are mediated through its receptor CX3CR1 which is widely expressed on different cell types including monocytes/macrophages, NK cells, cytotoxic T cells, B cells, smooth muscle cells, tumor cells, microglia, and neurons. Given that, CX3CL1/CX3CR1 axis is found to play an important role in the pathophysiology of many inflammatory, infectious, neurological and neoplastic conditions. In regard with obesity/T2D, the emerging data support that CX3CL1/CX3CR1 axis promotes inflammation and, therefore, therapeutic targeting of this axis represents a promising translational approach which can be achieved, in principle, by: (1) controlling ligand (CX3CL1) shedding by using antagonists of ADAM-10/17 or cathepsin S; and/or (2) blocking cognate receptor (CX3CR1) by using specific antibodies or clinical grade CX3CR1 antagonists. These translational strategies hold promise for future studies targeting the CX3CL1/CX3CR1 axis to treat inflammation associated with metabolic diseases.
Overall, these correlative data support the fractalkine as a marker for metabolic inflammation in T2D patients; nonetheless, further studies involving larger multicenter cohorts will be required to validate these preliminary findings. It also remains to be seen whether fractalkine has a causal relationship with the elevation of these inflammatory proteins in T2D pateints and/or which inflammatory chemokines/cytokines can regulate the induction of fractalkine, individually or synergistically.
Taken together, our data show that plasma fractalkine levels were significantly higher in T2D patients as compared with non-diabetic individuals. Fractalkine levels associated differentially with proinflammatory chemokines/cytokines as well as systemic CRP concentrations in diabetic and non-diabetic individuals which may have significant prognostic or therapeutic implications for T2D in humans.
Body mass index
Fasting blood glucose
Free fatty acid
Macrophage inflammatory protein
Oral glucose tolerance test
The authors thank KFAS for financial support. The authors also feel indebted to all individuals included in this study for their cooperation and voluntary participation.
This study was supported by funds from Kuwait Foundation for Advancement of Sciences (KFAS) (Grant # RA-2011-015).
Availability of data and material
All data generated or analyzed during this study are included in this published article.
SS guided experiments, analyzed and interpreted data and wrote the manuscript; NA performed most of experimental work, collected data, and helped with graphics; HA guided and supervised multiplex immunoassays, and also provided technical feedback; AAR conducted experiments; AW performed experimental work; AAH helped with blood sampling for experimental work; SA was involved in participant recruitment, sampling and data processing; SAB was involved in experimental work; SAZ was involved in patient assessment, informed consenting and recruitment; and RA wrote the proposal, procured funds, analyzed/interpreted data and wrote manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the ethics committee of Dasman Diabetes Institute, Kuwait (Research proposal # RA-2011-015).
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