EMILIN-1 deficiency promotes chronic inflammatory disease through TGFβ signaling alteration and impairment of the gC1q/α4β1 integrin interaction.

Eliana Pivetta, Alessandra Capuano, Maddalena Vescovo, Eugenio Scanziani, Andrea Cappelleri, Gian Luca Rampioni Vinciguerra, Andrea Vecchione, Roberto Doliana, Maurizio Mongiat, Paola Spessotto

Matrix biology : journal of the International Society for Matrix Biology 2022 Aug

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Alterations in extracellular matrix (ECM) components that modulate inflammatory cell behavior have been shown to serve as early starters for multifactorial diseases such as fibrosis and cancer. Here, we demonstrated that loss of the ECM glycoprotein EMILIN-1 alters the inflammatory context in skin during IMQ-induced psoriasis, a disease characterized by a prominent inflammatory infiltrate and alteration of vessels that appear dilated and tortuous. Abrogation of EMILIN-1 expression or expression of the EMILIN-1 mutant E933A impairs macrophage polarization and leads to imbalanced tissue homeostasis. We found that EMILIN-1 deficiency is associated with dilated lymphatic vessels, increased macrophage recruitment and psoriasis severity. Importantly, the null or mutant EMILIN-1 background was characterized by the induction of a myofibroblast phenotype, which in turn drove macrophages towards the M1 phenotype. By using the transgenic mouse model carrying the E933A mutation in the gC1q domain of EMILIN-1, which abolishes the interaction with α4- and α9-integrins, we demonstrated that the observed changes in TGFβ signaling were due to both the EMI and gC1q domains of EMILIN-1. gC1q may exert multiple functions in psoriasis, in the context of a final, more consistent inflammatory condition by controlling skin homeostasis via interaction with both keratinocytes and fibroblasts, influencing non-canonical TGFβ signaling, and likely acting on lymphatic vessel structure and function. The analyses of human psoriatic lesions, in which lower levels of EMILIN-1 were present with a very rare association with lymphatic vessels, support the multifaceted role of this ECM component in the skin inflammatory scenario. Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Eliana Pivetta, Alessandra Capuano, Maddalena Vescovo, Eugenio Scanziani, Andrea Cappelleri, Gian Luca Rampioni Vinciguerra, Andrea Vecchione, Roberto Doliana, Maurizio Mongiat, Paola Spessotto. EMILIN-1 deficiency promotes chronic inflammatory disease through TGFβ signaling alteration and impairment of the gC1q/α4β1 integrin interaction. Matrix biology : journal of the International Society for Matrix Biology. 2022 Aug;111:133-152