Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

Cells. 2022 Dec 15;11(24):4070. doi: 10.3390/cells11244070.


NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil "explosion" and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process.

Keywords: NETosis; biomarker; citrullination; histones; progression; sepsis; septic shock.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Citrullination
  • Endothelial Cells / metabolism
  • Endothelium / metabolism
  • Extracellular Traps* / metabolism
  • Histones / metabolism
  • Humans
  • Inflammation / metabolism
  • Sepsis* / metabolism


  • Histones

Grants and funding

R.O.-V. is supported by Contratos PFIS grant (FI20/00202) from AES-ISCIII and co-financed by the European Regional Development Fund (ERDF). J.B.-G. is supported by a Contratos i-PFIS grant (IFI18/00015) and co-financed by the European Social Fund. A B P. is supported by Contratos PFIS grant (FI18/00323) from AES-ISCIII. E N.-S. is supported by a grant (CIAPOT/2021/15) from Generalitat Valenciana. J.L.G.-G. thanks INCLIVA and GVA for the starting grants (GV/2014/132) and AES2016 (ISCIII) for grant numbers PI16/01036 and PI19/00994, co-financed by the European Regional Development Fund (ERDF). S.N. and C.H. thank AES (ISCIII) for grant numbers PI16/00229 and PI19/01714, co-financed by the European Regional Development Fund (ERDF), and Generalitat Valenciana for grant number CIAICO 2021/211. J.L.G.-G. and F.V.P. thank Grand Challenges Canada and the Spanish Ministry of Economy and Competitiveness, ISCIII through CIBERer (Biomedical Network Research Center for Rare Diseases and INGENIO2010). The authors would like to thank INCLIVA’s Biobank, MEC, ISCIII, and FEDER for grant PT13/0010/0004.