Citrullination in normal physiology
     ‐ Keratinization (keratin, trichohyalin, filaggrin) [17]

Nervous system
     ‐ Myelin sheath stability
     ‐ Plasticity of the brain [17]

Gene regulation
     ‐ P53 pathway [18‐23]
     ‐ Estrogen pathway [24,25]

Citrullination in pathophysiology
Innate immune responses
     ‐ PAD4‐catalysed histone hypercitrullination is essential in NET formation [26]
     ‐ PAD2 interacts with inhibitor κB kinase, and suppresses NF‐κB activity in macrophages after
        lipopolysaccharide stimulation [27]

     ‐ Citrullinated CXCL8
          1) has reduced affinity to glycosaminoglycans
          2) is resistant to thrombin/plasmin‐dependent cleavage
          3) is unable to attract neutrophils to the peritoneum
          4) can more efficiently recruit neutrophils into the blood circulation [28]
     ‐ Citrullinated CXCL12 has reduced effects through CXCR4 [29]
     ‐ Citrullinated CXCL10 and CXCL11 have decreased chemoattracting and signalling capacity through
        CXCR3 [30]

Effects of cytokines
     ‐ TNF induces the translocation of PAD4 to the nucleus [31]

     ‐ Hypocitrullination of CK1 [27]

     ‐ Increased tissue citrullination [9]
     ‐ Increased tissue and serum PAD4 [32,33]
     ‐ PAD4 interference with p53 pathway [34]
     ‐ Citrullination alters AT and CK [9,32,35]

Rheumatoid arthritis
     ‐ Triggering of protein citrullination, followed by ACPA generation and disease onset, induced by
          1)Genetic factors (HLADRB1, PTPN22)[36,37]]
          2)Environmental factors (infection, smoking) [16,38]

Multiple sclerosis
      ‐ Hypercitrullination of MBP [39]
Table 1: Roles of PADs and citrullination in (patho) physiology.