Immune cell - lipid crosstalk between intestinal leukocytes and modified ApoA-I as a novel mechanism in CKD aggravated atherosclerosis

Clin Res Cardiol (2026). DOI 10.1007/s00392-026-02870-1
M. Neuhaus (Aachen)¹, A. Bonnin-Márquez (Aachen)², L. Quintana (Aachen)¹, N. Tabaza (Aachen)¹, M. Reugels (Aachen)¹, N. Ganesh (Aachen)¹, M. Sausen (Aachen)¹, K. Müser (Aachen)¹, S. Just (Aachen)¹, R. Salagundi (Aachen)¹, B. Kurt (Aachen)¹, M. Gesper (Aachen)¹, B. A. Kappel (Aachen)¹, J. Spießhöfer (Aachen)³, P. Boor (Aachen)⁴, V. Jankowski (Aachen)², J. Jankowski (Aachen)², M. Lehrke (Traunstein)⁵, C. V. Schneider (Aachen)⁶, N. Marx (Aachen)¹, E. Van der Vorst (Aachen)², F. Kahles (Aachen)^1
1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; ²Uniklinik RWTH Aachen Institut für Molekulare Herz-Kreislaufforschung (IMCAR) Aachen, Deutschland; ³Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; ⁴Uniklinik RWTH Aachen Institut für Pathologie Aachen, Deutschland; ⁵Kliniken Südostbayern (KSOB) Kardiologie Traunstein, Deutschland; ⁶Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin Aachen, Deutschland

Background: Patients with chronic kidney disease (CKD) show aggravated atherosclerosis and vascular complications, thereby representing a high-risk patient population with a substantial unmet need for novel therapeutic targets to improve their prognosis. We recently observed that patients with CKD exhibit a stage-dependent increase in post-translational guanidinylation of Apolipoprotein A-I (ApoA-I), the primary protein of high-density lipoproteins (HDL), with this modification altering ApoA-I from a protective to a pro-inflammatory protein. Here we studied whether CKD-induced guanidinylation of ApoA-I plays a role for systemic inflammation and atherosclerosis formation.

Methods and Results: To investigate the effects of CKD-modified ApoA-I we administered guanidinylated ApoA-I compared to unmodified ApoA-I as control to mice and performed comprehensive FACS analysis of different immune cell compartments after 48h. Interestingly, guanidinylated ApoA-I selectively upregulated β7⁺ intraepithelial leukocytes (IELs) (1.9-fold increase, p<0.05), an intestinal immune cell population, which we recently found to be pro-atherogenic. We observed no significant differences in leukocytes in other organs after treatment with guanidinylated ApoA-I. Consistently, experimental CKD induced by 5/6 nephrectomy caused a significant increase in β7⁺ IELs in mice. To investigate the functional relevance of modified ApoA-I and intestinal immune cells in CKD-induced atherosclerosis, we performed 5/6 nephrectomy and induced atherosclerosis by PCSK9 virus injection and high-cholesterol diet (HCD) in ApoA-I^–/– and Integrin-β7^–/– mice, which are selectively deficient for intestinal immune cells. After 16 weeks mice lacking ApoA-I or intestinal immune cells were both protected from CKD-induced aggravated atherosclerosis and presented significant reductions in plaque volume and lesion size (p<0.05). Guanidinylated ApoA-I compared to unmodified ApoA-I markedly upregulated inflammatory (IFNγ, IL-6, and TNF-α) and proliferative (Ki-67) markers in human cultured lymphocytes in vitro. To translate these findings to humans, we analyzed circulating soluble Integrin-β7 levels in 47,981 participants of the UK Biobank. Individuals with CKD or renal failure exhibited significantly higher integrin-β7 plasma concentrations, which were further associated with a higher prevalence of CVD manifestations including heart failure and cardiovascular mortality.

Conclusion: Our findings suggest a novel gut immune cell lipid crosstalk as a mechanism linking CKD to accelerated atherosclerosis formation. We hypothesize that CKD-induced post-translational modifications of ApoA-I activate intestinal β7⁺ IELs to increase atherosclerosis formation. Future studies are needed to investigate if antibody-mediated targeting of β7⁺ IELs, as well as prevention of ApoA-I guanidinylation, may represent potential therapeutic strategies to reduce cardiovascular risk in CKD.