Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner

Abstract

Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14E138A/+- and Card14ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.

Gut Microbiota in Psoriasis

“…T-cell infiltration in active psoriatic skin creates a cytokine environment, mandating individual gene profiles in keratinocytes. This could overexpress various inflammatory mediators, enhancing local immune reactivity [ 48 , 49 ]. Moreover, better outcomes of trials addressing TNF-α inhibitors as a treatment in psoriasis patients reflect the critical role of this cytokine in the immunopathogenesis of psoriasis [ 50 , 51 ].…”

Allicin suppressed Escherichia coli-induced urinary tract infections by a novel MALT1/NF-κB pathway

“…Our previous study revealed that E. coli could activate the inflammation-related NF-κB pathway. 23 In this study, AKT/NF-κB was significantly activated by E. coli induced infection, which might be closely associated with perpetuated inflammation. The subsequent results of this study demonstrated that E. colimediated NF-κB activation is regulated by AKT or MALT1.…”

“…46,47 Accumulating evidence supports the crucial role of MALT1 in the pathogenesis of inflammatory disorders. [46][47][48][49] Moreover, MALT1 inductively combines with other molecules to assemble the complicated CARD-BCL10-MALT1 (CBM) signalosome, which is involved in the nuclear translocation of NF-κB. 46,49,50 As the classical inflammatory pathway, NF-κB is activated by the degradation of IκBα, which is regulated by the phosphorylation of AKT.…”

“…The injection was repeated after 4 hours as previously described. 23,24 Rats were treated with allicin intraperitoneally once per day for 1, 3, and 7 days post-injection. The usage method of allicin in the present study was selected based on previous in vivo studies.…”

MALT1 reflects inflammatory cytokines, disease activity, and its chronological change could estimate treatment response to infliximab in Crohn's disease patients

“…The present study identified that MALT1 was positively linked to inflammation (reflected by CRP, ESR, TNF‐α, IL‐1β, and IL‐17A) and disease activity (reflected by CDAI) in CD patients. Probable arguments would be that: (1) in terms of inflammation, MALT1 might stimulate the release of proinflammatory cytokines via activating B cell lymphoma/leukemia (BCL) 10, IL‐23/T17 axis, as well as NF‐κB and NLRP3 inflammasome 12,21,22 ; meanwhile, the formation of CARD11‐BCL10‐MALT1 complex played a key role in inflammation and immunity; thus, the dysregulated MALT1 might be linked with immunodeficiency or inflammation flare 23 ; therefore, a positive association was found between MALT1 and inflammation in CD patients. However, the linkage between MALT1 and IL‐6 was weakened.…”