Indoxyl sulfate exacerbates chronic inflammation and susceptibility to severe infection via modulating T-cell CD73/adenosine signaling in chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) is a major global health issue. Cardiovascular events and infections drive mortality in end-stage renal disease via immune dysregulation. The role of T-cell purinergic signaling and its modulation by indoxyl sulfate (IS) in CKD remains unclear. METHODS: Male Sprague-Dawley rats underwent 5/6 nephrectomy. The CKD + IS group received daily IS (100 μg/kg, intraperitoneally) for 24 weeks; control group received saline. Samples were collected 2-6 h post-injection. Sepsis was induced via cecal ligation and puncture. Splenic T-cell mRNA cluster of differentiation (CD) 73, CD39, A2A receptor (A2AR), P2X purinergic receptor (P2RX7), nuclear factor kappa-B (NF-κB) was quantified by quantitative real-time polymerase chain reaction. Plasma cytokines, vascular injury markers (asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1 (ICAM-1)), and myocardial markers (cardiac troponin T (cTnT), B-type natriuretic peptide (BNP)) were measured by enzyme-linked immunosorbent assay. Peripheral purine metabolites (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine (ADO)) were analyzed via ultra-high performance liquid chromatography-tandem mass spectrometry. Survival was monitored for 72 h. RESULTS: IS exacerbated baseline microinflammation, elevating plasma cytokines (interleukin 2 (IL-2), IL-6, IL-10, IL-17, tumor necrosis factor-alpha (TNF-α)) and T-cell NF-κB. This coincided with disrupted anti-inflammatory purinergic signaling, characterized by downregulated CD73/A2AR and reduced ADO. Post-infection, the CKD + IS group showed profound CD73 suppression and ADO depletion. Despite blunted cytokine surges, this group exhibited aggravated vascular and myocardial injury (elevated ADMA, ICAM-1, cTnT, BNP) and significantly higher 72-hour mortality. CONCLUSIONS: Indoxyl sulfate disrupts the T-cell CD73/ADO axis, promoting basal microinflammation while impairing anti-infective immunity and exacerbating organ damage during sepsis. Targeting the IS-CD73-ADO pathway offers a therapeutic strategy for restoring immune homeostasis in uremia.