Premium
IL ‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis
Author(s) -
Su Zhi,
Paulsboe Stephanie,
Wetter Joseph,
Salte Katherine,
Kannan Arun,
Mathew Sheeba,
Horowitz Amanda,
Gerstein Clare,
Namovic Marian,
Todorović Viktor,
Seagal Jane,
Edelmayer Rebecca M.,
Viner Michelle,
Rinaldi Lisa,
Zhou Li,
Leys Laura,
Huang Susan,
Wang Leyu,
Sadhukhan Ramkrishna,
Honore Prisca,
McGaraughty Steve,
Scott Victoria E.
Publication year - 2019
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13841
Subject(s) - psoriasis , inflammation , chemokine , immunology , tumor necrosis factor alpha , medicine
Abstract Psoriasis vulgaris ( PV ) results from activation of IL ‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin‐derived pro‐inflammatory cytokines, IL ‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL ‐23 and IL ‐36 pathways in PV . Herein, potential attenuation of skin inflammation in the IL ‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL ‐36 receptor ( IL ‐36R) was interrogated. Anti‐mouse IL ‐36R monoclonal antibodies ( mA bs) were generated and validated in vitro by inhibiting IL ‐36α‐induced secretion of CXCL 1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL 1 production in a novel acute model of IL ‐36α systemic injection in mice. In addition, anti‐ IL ‐36R mA bs inhibited tissue inflammation and inflammatory gene expression in an IL ‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL ‐36 signalling in IL ‐23/Th17 pathway, the ability of anti‐ IL ‐36R mA bs to inhibit skin inflammation in an IL ‐23 ear injection model was assessed. Inhibiting the IL ‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, these data suggest a role for IL ‐36 signalling in the IL ‐23/Th17 signalling axis in PV.