bims-nocaut 2023-03-05 papers

Issue of 2023–03–05
four papers selected by
Quentin Frenger, University of Strasbourg

Front Immunol. 2022 ;13 1079962

SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure.

Anugraha Gandhirajan, Sanjoy Roychowdhury, Christopher Kibler, Emily Cross, Susamma Abraham, Annett Bellar, Laura E Nagy, Rachel Greenberg Scheraga, Vidula Vachharajani.

Alcohol abuse, reported by 1/8th critically ill patients, is an independent risk factor for death in sepsis. Sepsis kills over 270,000 patients/year in the US. We reported that the ethanol-exposure suppresses innate-immune response, pathogen clearance, and decreases survival in sepsis-mice via sirtuin 2 (SIRT2). SIRT2 is an NAD+-dependent histone-deacetylase with anti-inflammatory properties. We hypothesized that in ethanol-exposed macrophages, SIRT2 suppresses phagocytosis and pathogen clearance by regulating glycolysis. Immune cells use glycolysis to fuel increased metabolic and energy demand of phagocytosis. Using ethanol-exposed mouse bone marrow- and human blood monocyte-derived macrophages, we found that SIRT2 mutes glycolysis via deacetylating key glycolysis regulating enzyme phosphofructokinase-platelet isoform (PFKP), at mouse lysine 394 (mK394, human: hK395). Acetylation of PFKP at mK394 (hK395) is crucial for PFKP function as a glycolysis regulating enzyme. The PFKP also facilitates phosphorylation and activation of autophagy related protein 4B (Atg4B). Atg4B activates microtubule associated protein 1 light chain-3B (LC3). LC3 is a driver of a subset of phagocytosis, the LC3-associated phagocytosis (LAP), which is crucial for segregation and enhanced clearance of pathogens, in sepsis. We found that in ethanol-exposed cells, the SIRT2-PFKP interaction leads to decreased Atg4B-phosphorylation, decreased LC3 activation, repressed phagocytosis and LAP. Genetic deficiency or pharmacological inhibition of SIRT2 reverse PFKP-deacetylation, suppressed LC3-activation and phagocytosis including LAP, in ethanol-exposed macrophages to improve bacterial clearance and survival in ethanol with sepsis mice.

Keywords: LC3-associated phagocytosis; Sirtuin 2; ethanol-exposure; glycolysis; macrophage; phagocytosis; sepsis

DOI: https://doi.org/10.3389/fimmu.2022.1079962

Tuberculosis (Edinb). 2023 Feb 24. pii: S1472-9792(23)00024-0. [Epub ahead of print]139 102326

IL-27 inhibits anti- Mycobacterium tuberculosis innate immune activity of primary human macrophages.

Hailey Gollnick, Jamie Barber, Robert J Wilkinson, Sandra Newton, Ankita Garg.

Mycobacterium tuberculosis (M. tuberculosis) is an intracellular pathogen that primarily infects macrophages. Despite a robust anti-mycobacterial response, many times macrophages are unable to control M. tuberculosis. The purpose of this study was to investigate the mechanism by which the immunoregulatory cytokine IL-27 inhibits the anti-mycobacterial activity of primary human macrophages. We found concerted production of IL-27 and anti-mycobacterial cytokines by M. tuberculosis-infected macrophages in a toll-like receptor (TLR) dependent manner. Notably, IL-27 suppressed the production of anti-mycobacterial cytokines TNFα, IL-6, IL-1β, and IL-15 by M. tuberculosis-infected macrophages. IL-27 limits the anti-mycobacterial activity of macrophages by reducing Cyp27B, cathelicidin (LL-37), LC3B lipidation, and increasing IL-10 production. Furthermore, neutralizing both IL-27 and IL-10 increased the expression of proteins involved in LC3-associated phagocytosis (LAP) pathway for bacterial clearance, namely vacuolar-ATPase, NOX2, and RUN-domain containing protein RUBCN. These results implicate IL-27 is a prominent cytokine that impedes M. tuberculosis clearance.

Keywords: Human macrophages(3), innate immunity(4), cytokines(5); IL-27(1); M. tuberculosis(2)

DOI: https://doi.org/10.1016/j.tube.2023.102326

PLoS Biol. 2023 Feb;21(2): e3002002

AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research.

Hallvard Lauritz Olsvik, Terje Johansen.

In this issue of PLOS Biology, Ibrahim and colleagues demonstrate how AlphaFold-multimer, an artificial intelligence-based structure prediction tool, can be used to identify sequence motifs binding to the ATG8 family of proteins central to autophagy.

DOI: https://doi.org/10.1371/journal.pbio.3002002

Front Cell Dev Biol. 2023 ;11 1132696

You are what you eat and how you digest it! A discussion on inflammatory efferocytosis.

Maria C Tanzer.

Efferocytosis is a process by which phagocytes remove dead or dying cells. It is considered anti-inflammatory, as the removal process reduces potential inflammatory molecules originating from dead cells and results in the reprogramming of macrophages to an anti-inflammatory state. However, engulfment of infected dead cells, deregulated phagocytosis and perturbed digestion of apoptotic bodies induce inflammatory signalling pathways during efferocytosis. The affected inflammatory signalling molecules and the mechanism of activation are largely unknown. I discuss how the choice of dead cell cargo, the type of ingestion, and the digestion efficiency can influence phagocyte programming in the context of disease. I also present the latest findings, highlight knowledge gaps, and propose selected experimental approaches to fill them.

Keywords: LC3-associated phagocytosis; cell death; efferocytosis; inflammation; phagolysosome

DOI: https://doi.org/10.3389/fcell.2023.1132696