bims-nocaut 2023-04-02 papers

Issue of 2023‒04‒02
three papers selected by
Quentin Frenger
University of Strasbourg

J Autoimmun. 2023 Mar 29. pii: S0896-8411(23)00039-2. [Epub ahead of print]136 103030

Autophagy pathways in autoimmune diseases.

Christian W Keller, Iannis E Adamopoulos, Jan D Lünemann.

Autophagy comprises a growing range of cellular pathways, which occupy central roles in response to energy deprivation, organelle turnover and proteostasis. Over the years, autophagy has been increasingly linked to governing several aspects of immunity, including host defence against various pathogens, unconventional secretion of cytokines and antigen presentation. While canonical autophagy-mediated antigen processing in thymic epithelial cells supports the generation of a self-tolerant CD4+ T cell repertoire, mounting evidence suggests that deregulated autophagy pathways contribute to or sustain autoimmune responses. In animal models of multiple sclerosis (MS), non-canonical autophagy pathways such as microtubule-associated protein 1 A/1 B-light chain 3 (LC3)-associated phagocytosis can contribute to major histocompatibility complex (MHC) class II presentation of autoantigen, thereby amplifying autoreactive CD4+ T cell responses. In systemic lupus erythematosus (SLE), increased type 1 interferon production is linked to excessive autophagy in plasmacytoid dendritic cells (DCs). In rheumatoid arthritis (RA), autophagy proteins contribute to pathological citrullination of autoantigen. Immunotherapies effective in autoimmune diseases modulate autophagy functions, and strategies harnessing autophagy pathways to restrain autoimmune responses have been developed. This review illustrates recent insights in how autophagy, distinct autophagy pathways and autophagy protein functions intersect with the evolution and progression of autoimmune diseases, focusing on MS, SLE and RA.

Keywords: Antigen presentation; Autoimmunity; Autophagy; Multiple sclerosis; Rheumatoid arthritis; Systemic lupus erythematosus

DOI: https://doi.org/10.1016/j.jaut.2023.103030

bioRxiv. 2023 Mar 14. pii: 2023.03.14.532586. [Epub ahead of print]

Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice.

Anuradha Dhingra, John W Tobias, Kathleen Boesze-Battaglia.

LC3b ( Map1lc3b ) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b, to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis and neuroprotection. In a mouse model of retinal lipid steatosis - mice lacking LC3b ( LC3b -/- ), we observed increased lipid deposition, metabolic dysregulation and enhanced inflammation. Herein we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b -/- mice revealed 1533 DEGs, with âˆ¼73% up-regulated and 27% down-regulated. Enriched gene ontology (GO) terms included inflammatory response (up-regulated DEGs), fatty acid metabolism and vascular transport (down-regulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.

DOI: https://doi.org/10.1101/2023.03.14.532586

Front Immunol. 2023 ;14 1142492

Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis.

Sarit Cohen-Kedar, Efrat Shaham Barda, Keren Masha Rabinowitz, Danielle Keizer, Hanan Abu-Taha, Shoshana Schwartz, Kawsar Kaboub, Liran Baram, Eran Sadot, Ian White, Nir Wasserberg, Meirav Wolff-Bar, Adva Levy-Barda, Iris Dotan.

Background: Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3-associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles via LAP.Methods: Colonic (n=18) and ileal (n=4) organoids from individuals undergoing bowel resection were grown as monolayers. Fluorescent-dye conjugated zymosan (β-glucan particle), heat-killed- and UV inactivated C. albicans were applied to differentiated organoids and to human IEC lines. Confocal microscopy was used for live imaging and immuno-fluorescence. Quantification of phagocytosis was carried out with a fluorescence plate-reader.
Results: zymosan and C. albicans particles were phagocytosed by monolayers of human colonic and ileal organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases.
Conclusions: Our results show that human IECs sense luminal fungal particles and internalize them via LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi.

Keywords: Candida albicans; LC3-associated phagocytosis; dectin-1; intestinal epithelial cells; organoids

DOI: https://doi.org/10.3389/fimmu.2023.1142492