IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI

Int J Mol Sci. 2025 Jun 2;26(11):5348. doi: 10.3390/ijms26115348.

Abstract

Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation.

Methods: We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified.

Results: In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: β = 0.34, 95% CI [0.16-0.53], p = 0.001, circulating leukocytes: β = 0.92, 95% CI [0.07-1.77], p = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (rs = 0.40, p = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (β = 1.15 95% CI [0.27-2.04], p = 0.013).

Conclusion: We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI.

Keywords: IL-6R; NETs; PAD4; STEMI; coronary thrombus; inflammation.

MeSH terms

  • Aged
  • Extracellular Traps* / metabolism
  • Female
  • Humans
  • Interleukin-6 / blood
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Leukocytes / metabolism
  • Male
  • Middle Aged
  • Neutrophils / metabolism
  • Protein-Arginine Deiminase Type 4* / blood
  • Protein-Arginine Deiminase Type 4* / genetics
  • Protein-Arginine Deiminase Type 4* / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-6* / genetics
  • Receptors, Interleukin-6* / metabolism
  • ST Elevation Myocardial Infarction* / blood
  • ST Elevation Myocardial Infarction* / genetics
  • ST Elevation Myocardial Infarction* / metabolism
  • ST Elevation Myocardial Infarction* / pathology
  • Signal Transduction*
  • Troponin T / blood

Substances

  • Protein-Arginine Deiminase Type 4
  • Receptors, Interleukin-6
  • Interleukin-6
  • Troponin T
  • PADI4 protein, human
  • IL6R protein, human
  • RNA, Messenger