bims-traimu 2023-07-09 papers

Issue of 2023–07–09
five papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2023 ;14 1183066

Trained immunity as a potential target for therapeutic immunomodulation in Duchenne muscular dystrophy.

Basil J Petrof, Tom Podolsky, Salyan Bhattarai, Jiahui Tan, Jun Ding.

Dysregulated inflammation involving innate immune cells, particularly of the monocyte/macrophage lineage, is a key contributor to the pathogenesis of Duchenne muscular dystrophy (DMD). Trained immunity is an evolutionarily ancient protective mechanism against infection, in which epigenetic and metabolic alterations confer non-specific hyperresponsiveness of innate immune cells to various stimuli. Recent work in an animal model of DMD (mdx mice) has shown that macrophages exhibit cardinal features of trained immunity, including the presence of innate immune system "memory". The latter is reflected by epigenetic changes and durable transmissibility of the trained phenotype to healthy non-dystrophic mice by bone marrow transplantation. Mechanistically, it is suggested that a Toll-like receptor (TLR) 4-regulated, memory-like capacity of innate immunity is induced at the level of the bone marrow by factors released from the damaged muscles, leading to exaggerated upregulation of both pro- and anti-inflammatory genes. Here we propose a conceptual framework for the involvement of trained immunity in DMD pathogenesis and its potential to serve as a new therapeutic target.

Keywords: chronic inflammatory diseases; immune memory; innate immunity; macrophages; mdx mouse; muscular dystrophies; sterile inflammation

DOI: https://doi.org/10.3389/fimmu.2023.1183066

J Leukoc Biol. 2023 Jul 04. pii: qiad076. [Epub ahead of print]

ATF2 orchestrates macrophage differentiation and activation to promote antibacterial responses.

Nusrah Rajabalee, Hannah Siushansian, Milani Weerapura, Stefania Berton, Fjolla Berbatovci, Breana Hooks, Michele Geoffrion, Dabo Yang, Mary-Ellen Harper, Katey Rayner, Alexandre Blais, Jim Sun.

The differentiation and activation of macrophages are critical regulatory programs that are central to host inflammation and defense against pathogens. However, the transcriptional regulatory pathways involved in these programs are not well understood. Herein, we demonstrate that the activity and expression of Activating Transcription Factor 2 (ATF2) is precisely regulated during primary human monocyte to macrophage differentiation, and that its activation is linked to M1 polarization and antibacterial responses. Genetic perturbation experiments demonstrated that deletion of ATF2 (THP-ΔATF2) resulted in irregular and abnormal macrophage morphology, whereas macrophages overexpressing ATF2 (THP-ATF2) developed round and pancake-like morphology, resembling classically activated (M1) macrophages. Mechanistically, we show that ATF2 binds to the core promoter of PPM1A, a phosphatase that regulates monocyte-to-macrophage differentiation, to regulate its expression. Functionally, overexpression of ATF2 sensitized macrophages to M1 polarization, resulting in increased production of MHC Class II, IL-1β and IP-10, improved phagocytic capacity, and enhanced control of the intracellular pathogen Mycobacterium tuberculosis. Gene expression profiling revealed that overexpression of ATF2 reprogramed macrophages to promote antibacterial pathways enriched in chemokine signaling, metabolism and antigen presentation. Consistent with pathways analysis, metabolic profiling revealed that genetic overexpression or stimuli-induced activation of ATF2 alters the metabolic capacity of macrophages and primes these cells for glycolytic metabolism during M1 polarization or bacterial infection. Our findings reveal that ATF2 plays a central role during macrophage differentiation and M1 polarization to enhance the functional capacities of macrophages.

Keywords: Mycobacterium tuberculosis ; ATF2; innate immunity; macrophage polarization; metabolic reprogramming; monocyte-to-macrophage differentiation; transcription factors

DOI: https://doi.org/10.1093/jleuko/qiad076

Cell Rep. 2023 Jul 01. pii: S2211-1247(23)00737-4. [Epub ahead of print]42(7): 112726

Cytosolic LPS-induced caspase-11 oligomerization and activation is regulated by extended synaptotagmin 1.

Yilei Ma, Ru Zhao, Hui Guo, Qingchao Tong, Wallace Y Langdon, Weiwei Liu, Jun Zhang, Jian Zhang.

Caspase-11 (Casp-11) is known to induce pyroptosis and defends against cytosol-invading bacterial pathogens, but its regulation remains poorly defined. Here, we identified extended synaptotagmin 1 (E-Syt1), an endoplasmic reticulum protein, as a key regulator of Casp-11 oligomerization and activation. Macrophages lacking E-Syt1 exhibited reduced production of interleukin-1β (IL-1β) and impaired pyroptosis upon cytosolic lipopolysaccharide (LPS) delivery and cytosol-invasive bacterial infection. Moreover, cleavage of Casp-11 and its downstream substrate gasdermin D were significantly diminished in ESyt1-/- macrophages. Upon LPS stimulation, E-Syt1 underwent oligomerization and bound to the p30 domain of Casp-11 via its synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain. E-Syt1 oligomerization and its interaction with Casp-11 facilitated Casp-11 oligomerization and activation. Notably, ESyt1-/- mice were susceptible to infection by cytosol-invading bacteria Burkholderia thailandensis while being resistant to LPS-induced endotoxemia. These findings collectively suggest that E-Syt1 may serve as a platform for Casp-11 oligomerization and activation upon cytosolic LPS sensing.

Keywords: CP: Cell biology; CP: Immunology; E-Syt1; caspase-11; endotoxemia; host defense; oligomerization; pyroptosis

DOI: https://doi.org/10.1016/j.celrep.2023.112726

Cell Chem Biol. 2023 Jun 22. pii: S2451-9456(23)00186-1. [Epub ahead of print]

Proximity-labeling chemoproteomics defines the subcellular cysteinome and inflammation-responsive mitochondrial redoxome.

Tianyang Yan, Ashley R Julio, Miranda Villanueva, Anthony E Jones, Andréa B Ball, Lisa M Boatner, Alexandra C Turmon, Kaitlyn B Nguyễn, Stephanie L Yen, Heta S Desai, Ajit S Divakaruni, Keriann M Backus.

Proteinaceous cysteines function as essential sensors of cellular redox state. Consequently, defining the cysteine redoxome is a key challenge for functional proteomic studies. While proteome-wide inventories of cysteine oxidation state are readily achieved using established, widely adopted proteomic methods such as OxICAT, Biotin Switch, and SP3-Rox, these methods typically assay bulk proteomes and therefore fail to capture protein localization-dependent oxidative modifications. Here we establish the local cysteine capture (Cys-LoC) and local cysteine oxidation (Cys-LOx) methods, which together yield compartment-specific cysteine capture and quantitation of cysteine oxidation state. Benchmarking of the Cys-LoC method across a panel of subcellular compartments revealed more than 3,500 cysteines not previously captured by whole-cell proteomic analysis. Application of the Cys-LOx method to LPS-stimulated immortalized murine bone marrow-derived macrophages (iBMDM), revealed previously unidentified, mitochondrially localized cysteine oxidative modifications upon pro-inflammatory activation, including those associated with oxidative mitochondrial metabolism.

Keywords: TurboID; chemoproteomics; cysteine; cysteine oxidation; lipopolysaccharide; macrophages; mitochondria; proximity labeling

DOI: https://doi.org/10.1016/j.chembiol.2023.06.008