bims-traimu 2023-01-22 papers

Issue of 2023–01–22
six papers selected by
Yantong Wan, Southern Medical University

J Clin Invest. 2023 Jan 17. pii: e166467. [Epub ahead of print]133(2):

Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines.

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has resulted in much human suffering and societal disruption. The ChAdOx1 nCoV-19 vaccine against COVID-19 has had a crucial role in the fight against the pandemic. While ChAdOx1 nCoV-19 has been shown to induce adaptive B and T cell responses, which protect against COVID-19, in this issue of the JCI, Murphy et al. show that this vaccine also induces trained innate immunity. This finding contributes to a better understanding of the complex immunological effects of adenoviral-based vaccines, provides the possibility of clinically relevant heterologous effects of these vaccines, and suggests that other adenoviral-based vaccines may induce trained immunity.

DOI: https://doi.org/10.1172/JCI166467

Cardiovasc Res. 2023 Jan 19. pii: cvad003. [Epub ahead of print]

Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities.

Ioannis Mitroulis, George Hajishengallis, Triantafyllos Chavakis.

Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favor chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.

DOI: https://doi.org/10.1093/cvr/cvad003

Biomedicines. 2023 Jan 11. pii: 183. [Epub ahead of print]11(1):

Inflammation Regulation by Bacterial Molecular Patterns.

Svetlana V Guryanova, Anastasiya Kataeva.

Stimulation of innate immunity by bacterial molecular patterns can induce an enhanced cellular immune response to pathogens that are associated with innate immune memory shaped by epigenetic changes. Immunological memory can be expressed in the acceleration/intensification of inflammation, as well as in the exact opposite-to maintain tolerance and non-response to a repeated stimulus. Tolerance is one of the central concepts of immunity and is ensured by the consistency of all parts of the immune response. The severe consequences of inflammation force researchers to study in detail all stages of the downstream pathways that are activated after exposure to a stimulus, while the formation of non-response to a pro-inflammatory stimulus has not yet received a detailed description. Elucidation of the mechanism of tolerance is an urgent task for the prevention and treatment of inflammatory diseases. The aim of this investigation was to study the dynamic changes in the gene expression of A20 and ATF3, the inflammation suppressors, against the background of the expression of the genes of the innate immunity receptors TLR4 and NOD2 and the pro-inflammatory cytokine TNF-α under the influence of TLR4 and NOD2 agonists, lipopolysaccharide (LPS) and glucosaminylmuramyl dipeptide (GMDP). The mechanism of inflammation regulation by bioregulators of bacterial origin-LPS and GMDP-was evaluated in vitro in human peripheral blood mononuclear cells and in vivo after i.p. administration of LPS and GMDP to mice. Gene expression was assessed by RT-PCR. Innate immune receptors and the pro-inflammatory cytokine TNF-α were found to develop early in response to LPS and GMDP, both in vitro and in vivo. Genes of cytosolic proteins controlling inflammation (A20 and ATF3) were expressed later. Prior exposure of the innate immune system to LPS and muramyl peptides may modulate host defense against acute inflammation. As a result of the study, new data were obtained on dynamic changes in deubiquitinase A20 and the transcription factor ATF3, which are involved in the limitation and suppression of inflammatory reactions caused by fragments of bacterial cell walls-LPS and GMDP. Thus, bioregulators of bacterial origin LPS and GMDP, along with pro-inflammatory factors, activate the expression of genes that suppress inflammation, which should be considered when analyzing data from studies of the pro-inflammatory properties of LPS and GMDP and when developing drugs based on them.

Keywords: A20; ATF3; GMDP; LPS; NOD2; TLR4; TNF-α; innate immune memory; innate immunity; lipopolysaccharide; muramyl peptide; tolerance

DOI: https://doi.org/10.3390/biomedicines11010183

Cell Syst. 2023 Jan 11. pii: S2405-4712(22)00500-2. [Epub ahead of print]

Quantifying stimulus-response specificity to probe the functional state of macrophages.

Katherine M Sheu, Aditya A Guru, Alexander Hoffmann.

Immune sentinel macrophages initiate responses to pathogens via hundreds of immune response genes. Each immune threat demands a tailored response, suggesting that the capacity for stimulus-specific gene expression is a key functional hallmark of healthy macrophages. To quantify this property, termed "stimulus-response specificity" (SRS), we developed a single-cell experimental workflow and analytical approaches based on information theory and machine learning. We found that the response specificity of macrophages is driven by combinations of specific immune genes that show low cell-to-cell heterogeneity and are targets of separate signaling pathways. The "response specificity profile," a systematic comparison of multiple stimulus-response distributions, was distinctly altered by polarizing cytokines, and it enabled an assessment of the functional state of macrophages. Indeed, the response specificity profile of peritoneal macrophages from old and obese mice showed characteristic differences, suggesting that SRS may be a basis for measuring the functional state of innate immune cells. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords: context dependence; gene regulatory mechanisms; information theory; innate immune function; machine learning; macrophage polarization; macrophages; response specificity; sentinel cells

DOI: https://doi.org/10.1016/j.cels.2022.12.012

Biomedicines. 2022 Dec 27. pii: 64. [Epub ahead of print]11(1):

The Latest Approach of Immunotherapy with Endosomal TLR Agonists Improving NK Cell Function: An Overview.

Irene Veneziani, Claudia Alicata, Lorenzo Moretta, Enrico Maggi.

Toll-like receptors (TLRs) are the most well-defined pattern recognition receptors (PRR) of several cell types recognizing pathogens and triggering innate immunity. TLRs are also expressed on tumor cells and tumor microenvironment (TME) cells, including natural killer (NK) cells. Cell surface TLRs primarily recognize extracellular ligands from bacteria and fungi, while endosomal TLRs recognize microbial DNA or RNA. TLR engagement activates intracellular pathways leading to the activation of transcription factors regulating gene expression of several inflammatory molecules. Endosomal TLR agonists may be considered as new immunotherapeutic adjuvants for dendritic cell (DC) vaccines able to improve anti-tumor immunity and cancer patient outcomes. The literature suggests that endosomal TLR agonists modify TME on murine models and human cancer (clinical trials), providing evidence that locally infused endosomal TLR agonists may delay tumor growth and induce tumor regression. Recently, our group demonstrated that CD56bright NK cell subset is selectively responsive to TLR8 engagement. Thus, TLR8 agonists (loaded or not to nanoparticles or other carriers) can be considered a novel strategy able to promote anti-tumor immunity. TLR8 agonists can be used to activate and expand in vitro circulating or intra-tumoral NK cells to be adoptively transferred into patients.

Keywords: Toll-like receptor agonists; cancer immunotherapy; endosomal Toll-like receptors; natural killer cells

DOI: https://doi.org/10.3390/biomedicines11010064