bims-traimu 2023-06-25 papers

Issue of 2023–06–25
four papers selected by
Yantong Wan, Southern Medical University

Cell Rep. 2023 Jun 16. pii: S2211-1247(23)00669-1. [Epub ahead of print]42(6): 112658

Dimethyl itaconate induces long-term innate immune responses and confers protection against infection.

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.

Keywords: CP: Immunology; glutathione; infection; innate immunity; itaconate; metabolism; monocytes; trained immunity

DOI: https://doi.org/10.1016/j.celrep.2023.112658

Microbes Infect. 2023 Jun 20. pii: S1286-4579(23)00077-1. [Epub ahead of print] 105174

The gut microbiota composition has no predictive value for the endotoxin-induced immune response or development of endotoxin tolerance in humans in vivo.

Niklas Bruse, Aron Jansen, Jelle Gerretsen, Danielle Rijbroek, Kiedo Wienholts, Melissa Arron, Harry van Goor, Thomas H A Ederveen, Peter Pickkers, Matthijs Kox.

BACKGROUND: It is largely unknown whether the gut microbiome regulates immune responses in humans. We determined relationships between the microbiota composition and immunological phenotypes in 108 healthy volunteers, using 16S sequencing, an ex vivo monocyte challenge model, and an in vivo challenge model of systemic inflammation induced by lipopolysaccharide (LPS).
RESULTS: Significant associations were observed between the microbiota composition and ex vivo monocytic cytokine responses induced by several stimuli, most notably IL-10 production induced by Pam3Cys, P. aeruginosa and C. albicans, although the explained variance was rather low (0.3 to 4.8%). Furthermore, a number of pairwise correlations between Blautia, Bacteroides and Prevotella genera and cytokine production induced by these stimuli were identified. LPS administration induced a profound transient in vivo inflammatory response. A second LPS challenge one week after the first resulted in a severely blunted response, reflecting endotoxin tolerance. However, no significant relationships between microbiota composition and in vivo parameters of inflammation or tolerance were found (explained variance ranging from 0.4 to 1.5%, ns).
CONCLUSIONS: The gut microbiota composition explains a limited degree of variance in ex vivo monocytic cytokine responses to several pathogenic stimuli, but no relationships with the LPS-induced in vivo immune response or tolerance was observed.

Keywords: 16S sequencing; Endotoxin; Gut microbiome; Lipopolysaccharide; Personalized Medicine; Tolerance

DOI: https://doi.org/10.1016/j.micinf.2023.105174

Mil Med Res. 2023 Jun 19. 10(1): 27

Single-cell transcriptome profiling of sepsis identifies HLA-DRlowS100Ahigh monocytes with immunosuppressive function.

Ren-Qi Yao, Peng-Yue Zhao, Zhi-Xuan Li, Yu-Yang Liu, Li-Yu Zheng, Yu Duan, Lu Wang, Rong-Li Yang, Hong-Jun Kang, Ji-Wei Hao, Jing-Yan Li, Ning Dong, Yao Wu, Xiao-Hui Du, Feng Zhu, Chao Ren, Guo-Sheng Wu, Zhao-Fan Xia, Yong-Ming Yao.

BACKGROUND: Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.
METHODS: We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9-/- mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.
RESULTS: ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRlowS100Ahigh monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.
CONCLUSIONS: This study identifies HLA-DRlowS100Ahigh monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.

Keywords: Human leukocyte antigen DR (HLA-DR); Immunosuppression; Monocytes; Myeloid-derived suppressor cells (MDSCs); Paquinimod; S100A; Sepsis; Single-cell analysis

DOI: https://doi.org/10.1186/s40779-023-00462-y

BMC Immunol. 2023 Jun 23. 24(1): 11

Prevention of M2 polarization and temporal limitation of differentiation in monocytes by extracellular ATP.

Benedikt F Scherr, Martin F Reiner, Flavia Baumann, Kerstin Höhne, Tobias Müller, Korcan Ayata, Joachim Müller-Quernheim, Marco Idzko, Gernot Zissel.

BACKGROUND: Elevated levels of extracellular adenosine triphosphate (ATP) modulate immunologic pathways and are considered to be a danger signal in inflammation, lung fibrosis and cancer. Macrophages can be classified into two main types: M1 macrophages are classically activated, pro-inflammatory macrophages, whereas M2 macrophages are alternatively activated, pro-fibrotic macrophages. In this study, we examined the effect of ATP on differentiation of native human monocytes into these macrophage subtypes. We characterized M1 and M2 like macrophages by their release of Interleukin-1beta (IL-1β) and Chemokine (C-C motif) ligand 18 (CCL18), respectively.
RESULTS: Monocytes were stimulated with ATP or the P2X7 receptor agonist Benzoylbenzoyl-ATP (Bz-ATP), and the production of various cytokines was analyzed, with a particular focus on CCL18 and IL-1β, along with the expression of different purinergic receptors. Over a 72 h period of cell culture, monocytes spontaneously differentiated to M2 like macrophages, as indicated by an increased release of CCL18. Immediate stimulation of monocytes with ATP resulted in a dose-dependent reduction in CCL18 release, but had no effect on the concentration of IL-1β. In contrast, delayed stimulation with ATP had no effect on either CCL18 or IL-1β release. Similar results were observed in a model of inflammation using lipopolysaccharide-stimulated human monocytes. Stimulation with the P2X7 receptor agonist Bz-ATP mimicked the effect of ATP on M2-macrophage differentiation, indicating that P2X7 is involved in ATP-induced inhibition of CCL18 release. Indeed, P2X7 was downregulated during spontaneous M2 differentiation, which may partially explain the ineffectiveness of late ATP stimulation of monocytes. However, pre-incubation of monocytes with PPADS, Suramin (unselective P2X- and P2Y-receptor blockers) and KN62 (P2X7-antagonist) failed to reverse the reduction of CCL18 by ATP.
CONCLUSIONS: ATP prevents spontaneous differentiation of monocytes into M2-like macrophages in a dose- and time-dependent manner. These effects were not mediated by P2X and P2Y receptors.

Keywords: ATP; CCL18; Differentiation; M2 macrophage; Monocyte

DOI: https://doi.org/10.1186/s12865-023-00546-3