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

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.

TRIM33 deficiency in monocytes and macrophages impairs resolution of colonic inflammation.

BACKGROUND: Mature myeloid cells play a crucial role in Crohn's disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. We and others have shown that TRIM33 is involved in the innate immune response and in the inflammatory response but TRIM33 role in intestinal inflammation is not known. In this study, we investigated the role of TRIM33 in myeloid cells during dextran sulfate sodium (DSS)-induced colitis. METHODS: We study the role of TRIM33 during DSS-induced colitis which mimics intestinal inflammation using mice deleted for Trim33 only in mature myeloid cells (Trim33-/- mice) FINDINGS: We first show that Trim33 mRNA level is decreased in CD patient's blood monocytes suggesting a role of TRIM33 in CD. Using Trim33-/- mice, we show that these mice display an impaired resolution of colonic inflammation with an increased number of blood and colon monocytes and a decreased number of colonic macrophages. Trim33-/- monocytes are less competent for recruitment and macrophage differentiation. Finally, during resolution of inflammation, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane-bound TNF that is associated with an increased number of colonic neutrophils. INTERPRETATION: Our study shows an important role of TRIM33 in monocytes/macrophages during DSS-induced colitis and suggests that the decreased expression of TRIM33 in CD patient's blood monocytes might not be a consequence but might be involved in CD progression. FUND: La Ligue contre le Cancer (équipe labelisée), INSERM, CEA, Université Paris-Diderot, Université Paris-Sud.