Infliximab Inhibits TNF-α-dependent Activation of the NLRP3/IL-1β Pathway in Acne Inversa

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Jul 12

PMID 38994066

Authors

Yanyan He

Wenzhu Wang

Juan Jiang

Yuanxing Shen

Baoxi Wang

Jiangning Chen

Min Li

Haoxiang Xu

Affiliations

Soon will be listed here.

Abstract

Background: Acne inversa (AI) is a refractory inflammatory skin disease, and TNF-α plays an important role in the pathogenesis of AI. By blocking TNF-α, infliximab (IFX) has been proven to be a promising method.

Objectives: To explore the underlying mechanisms of IFX treatment in AI patients.

Methods: In this research, we integrated transcriptome sequencing data from the samples of our patients with AI and the GEO database. skin culture of AI patients was conducted to evaluate the efficacy of IFX treatment. Animal studies and cell experiments were used to explore the therapeutic effect and mechanism of IFX treatment.

Results: Both TNF-α and NLRP3 inflammasome-related pathways were enriched in skin lesions of AI patients and murine AI models. After IFX treatment, the NLRP3 inflammasome-related pathway was effectively blocked, and the IL-1β level was normalized in AI skin explants and murine AI models. Mechanistically, IFX suppressed the NF-κB signaling pathway to lower the expression of NLRP3 and IL-1β in keratinocytes.

Conclusions: IFX treatment alleviated skin lesions in murine AI models and downregulated NLRP3 and IL-1β expression levels by inhibiting the NF-κB signaling pathway, which was helpful for understanding the mechanism of IFX therapy.

References

Frings V, Sennefelder H, Presser D, Goebeler M, Schmidt M . Altered NOX expression does not seem to account for epidermal NLRP3 inflammasome activation in hidradenitis suppurativa. Br J Dermatol. 2019; 181(2):391-392. DOI: 10.1111/bjd.17647. View

Frew J, Piguet V . Ex Vivo Models and Interpretation of Mechanistic Studies in Hidradenitis Suppurativa. J Invest Dermatol. 2020; 140(7):1323-1326. DOI: 10.1016/j.jid.2020.02.014. View

van der Zee H, De Ruiter L, van den Broecke D, Dik W, Laman J, Prens E . Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β. Br J Dermatol. 2011; 164(6):1292-8. DOI: 10.1111/j.1365-2133.2011.10254.x. View

Hotz C, Boniotto M, Guguin A, Surenaud M, Jean-Louis F, Tisserand P . Intrinsic Defect in Keratinocyte Function Leads to Inflammation in Hidradenitis Suppurativa. J Invest Dermatol. 2016; 136(9):1768-1780. DOI: 10.1016/j.jid.2016.04.036. View

Saunte D, Jemec G . Hidradenitis Suppurativa: Advances in Diagnosis and Treatment. JAMA. 2017; 318(20):2019-2032. DOI: 10.1001/jama.2017.16691. View

Jaeger T, Andres C, Grosber M, Zirbs M, Hein R, Ring J . Pyoderma gangrenosum and concomitant hidradenitis suppurativa--rapid response to canakinumab (anti-IL-1β). Eur J Dermatol. 2013; 23(3):408-10. DOI: 10.1684/ejd.2013.2018. View

Shih T, Lee K, Grogan T, De D, Shi V, Hsiao J . Infliximab in hidradenitis suppurativa: A systematic review and meta-analysis. Dermatol Ther. 2022; 35(9):e15691. PMC: 9539481. DOI: 10.1111/dth.15691. View

Moran B, Sweeney C, Hughes R, Malara A, Kirthi S, Tobin A . Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy. J Invest Dermatol. 2017; 137(11):2389-2395. DOI: 10.1016/j.jid.2017.05.033. View

Witte-Handel E, Wolk K, Tsaousi A, Irmer M, Mossner R, Shomroni O . The IL-1 Pathway Is Hyperactive in Hidradenitis Suppurativa and Contributes to Skin Infiltration and Destruction. J Invest Dermatol. 2018; 139(6):1294-1305. DOI: 10.1016/j.jid.2018.11.018. View

10.

Vossen A, Ardon C, van der Zee H, Lubberts E, Prens E . The anti-inflammatory potency of biologics targeting tumour necrosis factor-α, interleukin (IL)-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study. Br J Dermatol. 2019; 181(2):314-323. PMC: 6850593. DOI: 10.1111/bjd.17641. View

11.

Balato A, Caiazzo G, Annunziata M, Marasca C, Scala E, Cacciapuoti S . Anti-TNF-α therapy modulates mTORC1 signalling in hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2018; 33(1):e43-e45. DOI: 10.1111/jdv.15160. View

12.

Lopetuso L, Petito V, Zinicola T, Graziani C, Gerardi V, Arena V . Infliximab does not increase colonic cancer risk associated to murine chronic colitis. World J Gastroenterol. 2016; 22(44):9727-9733. PMC: 5124977. DOI: 10.3748/wjg.v22.i44.9727. View

13.

Shen J, Dai Z, Li Y, Zhu H, Zhao L . TLR9 regulates NLRP3 inflammasome activation via the NF-kB signaling pathway in diabetic nephropathy. Diabetol Metab Syndr. 2022; 14(1):26. PMC: 8815223. DOI: 10.1186/s13098-021-00780-y. View

14.

Markota cagalj A, Marinovic B, Bukvic Mokos Z . New and Emerging Targeted Therapies for Hidradenitis Suppurativa. Int J Mol Sci. 2022; 23(7). PMC: 8998913. DOI: 10.3390/ijms23073753. View

15.

Savage K, Flood K, Porter M, Kimball A . TNF-α inhibitors in the treatment of hidradenitis suppurativa. Ther Adv Chronic Dis. 2019; 10:2040622319851640. PMC: 6540495. DOI: 10.1177/2040622319851640. View

16.

He Y, Xu H, Li C, Zhang X, Zhou P, Xiao X . Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa. J Invest Dermatol. 2018; 139(1):124-134. DOI: 10.1016/j.jid.2018.07.020. View

17.

Haferland I, Wallenwein C, Ickelsheimer T, Diehl S, Wacker M, Schiffmann S . Mechanism of anti-inflammatory effects of rifampicin in an ex vivo culture system of hidradenitis suppurativa. Exp Dermatol. 2022; 31(7):1005-1013. DOI: 10.1111/exd.14531. View

18.

Wang J, Kang G, Lu H, de Marco A, Yuan H, Feng Z . Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF-α and IL-23p19 bioactivities. Clin Transl Med. 2024; 14(3):e1636. PMC: 10966562. DOI: 10.1002/ctm2.1636. View

19.

Matusiak L, Bieniek A, Szepietowski J . Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents?. Acta Derm Venereol. 2009; 89(6):601-3. DOI: 10.2340/00015555-0749. View

20.

van der Zee H, Laman J, De Ruiter L, Dik W, Prens E . Adalimumab (antitumour necrosis factor-α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study. Br J Dermatol. 2011; 166(2):298-305. DOI: 10.1111/j.1365-2133.2011.10698.x. View