IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

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 (mAbs) were generated and validated in vitro by inhibiting IL‐36α‐induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs 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 mAbs 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.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…Another severe subtype, called generalized pustular psoriasis, was found to result from an overactive IL-36 pathway (5). In agreement, neutralizing antibodies against IL-17A and IL-23 represent effective state-of-the-art therapies for the treatment of patients with psoriasis, whereas antagonizing IL-36 receptor antibodies are currently being investigated as a new therapy approach for psoriasis (6).…”

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin‐23 minicircles in mice

“…Hydrodynamic gene delivery is a commonly used in vivo transfection method that involves rapidly injecting a large volume of plasmid DNA into the lateral tail vein, which then forces the solution into the liver and transfects the hepatocytes. [16][17][18]24 In these studies, animals were hydrodynamically injected with IL-23 MC, causing a significant increase of IL-23 levels in both the plasma (F [14,207] = 21.55, P < 0.0001) and ear (F [14,150] = 21.21, P < 0.0001) ( Table 1). For the highest dose (3 lg), circulating plasma IL-23 levels were elevated as early as day 2 post-injection, and remained elevated throughout the 14-day study duration.…”

“…Repeated intradermal injection of IL‐23 to mice has been used as a mechanistic model that recapitulates many key features of psoriasis . These models have been useful in understanding skin inflammation associated with activation of this pathway and evaluating novel therapeutics.…”

“…6 Repeated intradermal injection of IL-23 to mice has been used as a mechanistic model that recapitulates many key features of psoriasis. [7][8][9][10][11][12][13][14] These models have been useful in understanding skin inflammation associated with activation of this pathway and evaluating novel therapeutics. An alternative means to augment endogenous IL-23 levels is to utilize hydrodynamic delivery of IL-23 minicircles (MC).…”

Getting ready for the next decade of Experimental Dermatology

“…essays on Skin Immunity, [1][2][3][4] and authoritative reviews and original research articles on (b) Cell Biology of Skin Immunity, [5][6][7] (c) Immunopathology of Atopic Dermatitis, [8][9][10][11][12] (d) Psoriasis [13][14][15] and (e) Bullous pemphigoid. [16] In addition, it covers (f) the Immunology of Wound Healing and, [17,18] and, finally, (g) Animal models in Skin Immunology Research.…”