Impaired reprogramming of the autophagy flux in maturing dendritic cells from crohn disease patients with core autophagy gene-related polymorphisms

ABSTRACT

Crohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A>G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C>T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges.

Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.

KEYWORDS:

• Autophagy flux
• Crohn disease
• dendritic cells
• single nucleotide polymorphism
• inflammation

Acknowledgements

This work was supported by Agence Nationale pour la Recherche (ANR-22-CE17-0054-02), Fondation pour la Recherche Médicale (Label FRM DEQ20170336729), Société Nationale Française de Gastro-Entérologie (SNFGE) and Association François Aupetit (AFA). We thank Pr. John H. Brumell and Pr. Nicolas Barnich for providing us with plasmids and bacteria, respectively). We also thank Célia Guillerminet, Guenaelle Lamiral and Aude Lavedrine for technical support, Marie Cariou for statistical analysis and Dr Patrice Codogno for critical reading of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2338574

Additional information

Funding

The work was supported by the Agence Nationale de la Recherche [ANR-22-CE17-0054-02]; Laboratoire d’Excellence Ecofect [ANR-11-LABX-0042]; Fondation pour la Recherche Médicale [DEQ20170336729].