CXCL12, CXCR4 Linked to Uric Acid-Induced Inflammation, Gouty Arthritis

The chemokine receptor CXCR4 and its ligand CXCL12 were associated with the pathogenesis of uric acid-induced inflammation and gouty arthritis, according to a study published in biomedicines.¹

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Chemokines, small, secreted chemotactic cytokines, play a role in cellular homeostasis, immune system activation, and inflammatory responses. They have also been linked to the pathogenesis of inflammation of diverse joint diseases and have been considered as possible therapeutic targets.²

“The CXCL12/CXCR4 axis has been implicated in the pathogenesis of several types of inflammatory arthritis and autoimmune diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS),” wrote a group of Korean investigators. “Evidence of the pathogenic role of CXCR4 and CXCL12 in uric acid-induced inflammation has not been presented. Thus, the aim of this study was to compare the CXCR4 and CXCL12 levels between gout patients and controls and to determine the role of these molecules in uric acid-induced inflammation.”

Forty adult male patients with intercritical gout and 27 age- and gender-matched controls were enrolled in the study. Data collected included current medication, age, gender, creatinine, estimated glomerular filtration rate (eGFR), uric acid, erythrocyte sedimentation rate (ESR), blood urea nitrogen, and C-reactive protein (CRP).

An enzyme-linked immunosorbent assay was utilized to assess the serum levels of interleukin-1β (IL-1β), IL-18, CXCR4, and CXCL12. The gene and protein expressions for these molecules were evaluated in human U937 cells that were incubated with monosodium urate (MSU) crystals using both real-time reverse transcription polymerase chain reaction and a Western blot analysis.

Patients with intercritical gout had higher CXCL12 levels, IL-18, and IL-1β when compared with controls; however, CXCR4 levels were not comparatively higher.

The CXCR4 level in patients with gout was linked to the serum IL-18 level, uric acid level, and uric acid/creatinine ration (r = 0.331, P = .037; r = 0.346, P = .028; and r = 0.361, P = .022, respectively). Gout patients exhibited a larger increase in the expression of the serum CXCL12 when compared with the controls (392.27 ± 247.54 vs 243.90 ± 184.03, P = .010). CXCR4 levels did not vary significantly between cohorts (45.45 ± 18.46 vs 47.45 ± 8.35, P = 0.550).

U937 cells treated with MSU crystals significantly induced the CXCL12 and CXCR4 mRNA and protein expression as well as IL-18 and IL-1β. The CXCL12 and CXCR4 expression was downregulated in cells transfects with IL-1β small interfering RNA (siRNA) or IL-18 siRNA when compared with non-transfected cells in the MSU crystal-induced inflammation.

Investigators noted limitations that may have impacted the interpretation of the results, including the small sample size of patients and controls. The expression of CXCL12 and CXCR4 was cross-sectionally analyzed, which hindered the ability to longitudinally confirm the change pattern of the molecules linked to medications or other inflammatory factors. An additional limitation was that the expression of CXCL12 and CXCR4 was evaluated using serum extracted from whole blood. Investigators argued that confirming the expression of these target molecules from peripheral blood mononuclear cells (PBMCs) may have been more effective.

“We found that gout patients showed a higher expression of CXCL12 and proinflammatory cytokines, including IL-1β and IL-18, than members of the control group,” investigators concluded. “Additionally, this study found that the expression of CXCL12 and CXCR4 could be regulated during NLRP3 inflammasome activation stimulated by MSU crystals in U937 macrophages. Therefore, chemokine CXCL12 and its receptor CXCR4 might be considered to be potent therapeutic targets in uric acid-induced NLRP3 inflammasome activation in gout patients.”

References

1. ^{Kim SK, Choe JY, Park KY. CXCL12 and CXCR4 as Novel Biomarkers in Uric Acid-Induced Inflammation and Patients with Gouty Arthritis. Biomedicines. 2023;11(3):649. Published 2023 Feb 21. doi:10.3390/biomedicines11030649}
2. ^{Haringman, J.J.; Ludikhuize, J.; Tak, P.P. Chemokines in joint disease: The key to inflammation. Ann. Rheum. Dis. 2004, 63, 1186–1194}