Citrullination in normal physiology
Epidermis
‐ 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]
Chemokines
‐ 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]
Psoriasis
‐ Hypocitrullination of CK1 [27]
Tumorigenesis
‐ 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 (HLA‐DRB1, PTPN22)[36,37]]
2)Environmental factors (infection, smoking) [16,38]
Multiple sclerosis
‐ Hypercitrullination of MBP [39] |
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