bims-nastce 2022-03-20 papers

Immune Netw. 2022 Feb;22(1): e13

The Role of T Cells in Obesity-Associated Inflammation and Metabolic Disease.

Chronic inflammation plays a critical role in the development of obesity-associated metabolic disorders such as insulin resistance. Obesity alters the microenvironment of adipose tissue and the intestines from anti-inflammatory to pro-inflammatory, which promotes low grade systemic inflammation and insulin resistance in obese mice. Various T cell subsets either help maintain metabolic homeostasis in healthy states or contribute to obesity-associated metabolic syndromes. In this review, we will discuss the T cell subsets that reside in adipose tissue and intestines and their role in the development of obesity-induced systemic inflammation.

Keywords: Insulin resistance; Metabolic diseases; Obese mice; Obesity-associated inflammation; T cells

DOI: https://doi.org/10.4110/in.2022.22.e13

Nat Commun. 2022 Mar 17. 13(1): 1440

Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23.

Lauriane Galle-Treger, Doumet Georges Helou, Christine Quach, Emily Howard, Benjamin P Hurrell, German R Aleman Muench, Pedram Shafiei-Jahani, Jacob D Painter, Andrea Iorga, Lily Dara, Juliet Emamaullee, Lucy Golden-Mason, Hugo R Rosen, Pejman Soroosh, Omid Akbari.

There has been a global increase in rates of obesity with a parallel epidemic of non-alcoholic fatty liver disease (NAFLD). Autophagy is an essential mechanism involved in the degradation of cellular material and has an important function in the maintenance of liver homeostasis. Here, we explore the effect of Autophagy-related 5 (Atg5) deficiency in liver CD11c+ cells in mice fed HFD. When compared to control mice, Atg5-deficient CD11c+ mice exhibit increased glucose intolerance and decreased insulin sensitivity when fed HFD. This phenotype is associated with the development of NAFLD. We observe that IL-23 secretion is induced in hepatic CD11c+ myeloid cells following HFD feeding. We demonstrate that both therapeutic and preventative IL-23 blockade alleviates glucose intolerance, insulin resistance and protects against NAFLD development. This study provides insights into the function of autophagy and IL-23 production by hepatic CD11c+ cells in NAFLD pathogenesis and suggests potential therapeutic targets.

DOI: https://doi.org/10.1038/s41467-022-29174-y

Cell. 2022 Mar 10. pii: S0092-8674(22)00195-7. [Epub ahead of print]

Spatial CRISPR genomics identifies regulators of the tumor microenvironment.

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFβ and TGFβ-mediated fibroblast activation, indicating that TGFβ-receptor loss on cancer cells increased TGFβ bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME.

Keywords: CRISPR screens; Socs1; TGF beta; cancer immunology; interferon gamma; lung cancer; spatial genomics; spatial transcriptomics; tumor clonality; tumor microenvironment

DOI: https://doi.org/10.1016/j.cell.2022.02.015