CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17–Mediated Psoriasiform Skin Inflammation In Vivo

Abstract

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

“…This suggests a similar mechanism of activation, via induction of an active CARD14 conformation and oligomerization necessary for CBM complex formation and downstream signaling events. In support of this model, a recent study showed that a single point mutation in CARD14 E138A, which renders CARD14 hyperactive, was sufficient to drive spontaneous psoriasis disease in mice (125). Inhibition of MALT1 protease activity effectively reduces cytokine and chemokine expression induced by overexpression of this hyperactive CARD14 mutant in human primary keratinocytes (126).…”

Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

“…A very recent study found that IL-17 and IL-22 promote keratinocyte stemness (Ekman et al, 2019). In two studies, it was shown that mice with a gain-of-function mutation of the card14 gene, a known risk locus for human psoriasis, developed spontaneous psoriasis-like skin inflammation triggered by IL-17 mostly derived from αβ T cells acting on keratinocytes (Mellett et al, 2018;Wang et al, 2018). This was mediated by intracellular CARMA2 accumulation and activation.…”

Histopathologic findings characteristic of CARD14‐associated papulosquamous eruption

“…CARD14 encodes a member of the membrane‐associated guanylate kinase family, and falls within PSORS2 , the psoriasis susceptibility 2 locus . CARD14 is known to activate NF‐κB, while increasing the expression of inflammatory factors including tumor necrosis factor alpha (TNFα), interleukin‐17 (IL‐17), chemokine ligand 8 (CXCL‐8), and interleukin‐36γ (IL‐36γ) . These are canonical pathways implicated in psoriasis.…”