Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses

Abstract

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…The observation that the abnormal Th2/Th17 cytokine profile of ARI PBMCs was partly normalized by a pan-PAD inhibitor and was recapitulated by overexpression of PADs strongly suggests that failure to suppress citrullination, but not failure to produce type I interferon, is the cause of the abnormal cytokine profile. In addition, the Th2/Th17 cytokine profile of ARI PBMCs is almost a mirror image of the ex vivo cytokine profile of mice treated with another pan-PAD inhibitor, BB-Cl-amidine (55). While it is still unclear how hypercitrullination causes the aberrant expression of Th2 and Th17 cytokines, our data have expanded the role of hypercitrullination in RA pathogenesis.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…This led to programs developing PAD inhibitors in RA, and these have shown significant promise. 118,119 Major drug-development programs have been initiated to target the M1 aminopepidase genes ERAP1 (MIM: 606832) and ERAP2 (MIM: 609497) because of their genetic associations with AS, psoriasis, IBD, Behcet disease (MIM: 109650), and the rare condition Birdshot retinopathy (MIM: 605808). 120 Bioinformatic follow-up of GWAS results has also been fruitful.…”

A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination

“…In the immune system, PAD4 promotes cytokine production by augmenting chromatin association of E2F-1 and decreasing HP1-mediated transcriptional repression of cytokine genes (74, 89). Moreover, PAD4 inhibitors were shown to decrease pro-inflammatory Th1 and Th17 responses and to increase anti-inflammatory Th2 responses both in vitro and in vivo (96). PAD inhibition also blocks the functional maturation of dendritic cells induced by toll-like receptor agonists (97).…”