bims-traimu 2023-08-27 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–08–27
ten papers selected by
Yantong Wan, Southern Medical University

Innate immune memory, trained immunity and nomenclature clarification.
Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis.
Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.
Clinical and Experimental Determination of Protection Afforded by BCG Vaccination against Infection with Non-Tuberculous Mycobacteria: A Role in Cystic Fibrosis?
Decreased Expression of CD314 by NK Cells Correlates with Their Ability to Respond by Producing IFN-γ after BCG Moscow Vaccination and Is Associated with Distinct Early Immune Responses.
Endotoxin-Tolerance Mimicking to Study TLR in Promotion of Tolerogenic DCs and Tr1 Cells.
Protective effect of β-glucan on Poly(I:C)-induced acute lung injury/inflammation: Therapeutic implications of viral infections in the respiratory system.
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
Study of Agonists of TLRs as Vaccine Adjuvants.
Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.

Nat Immunol. 2023 Sep;24(9): 1393-1394

Innate immune memory, trained immunity and nomenclature clarification.

George Hajishengallis, Mihai G Netea, Triantafyllos Chavakis.

DOI: https://doi.org/10.1038/s41590-023-01595-x
J Exp Med. 2023 11 06. pii: e20221388. [Epub ahead of print]220(11):

Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis.

Sreeparna Chakraborty, Abhalaxmi Singh, Li Wang, Xinge Wang, Mark A Sanborn, Zijing Ye, Mark Maienschein-Cline, Amitabha Mukhopadhyay, Balaji B Ganesh, Asrar B Malik, Jalees Rehman.

Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also enhances injury resolution to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) prechallenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis and functional assays showed greater capacity of trained AMs for efferocytosis of cellular debris and injury resolution. Single-cell high-dimensional mass cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AM subset with a proresolving phenotype. Reprogrammed AMs upregulated expression of the efferocytosis receptor MERTK mediated by the transcription factor KLF4. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal P. aeruginosa. Thus, our study has identified a subset of tissue-resident trained macrophages that prevent hyperinflammation and restore tissue homeostasis following repeated pathogen challenges.

DOI: https://doi.org/10.1084/jem.20221388
Cell. 2023 Aug 15. pii: S0092-8674(23)00796-1. [Epub ahead of print]

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Jin-Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma, Christopher N Parkhurst, Simon A Grassmann, Claire K Wingert, Paoline Laurent, Sai Ma, Lucinda Paddock, Isabella C Miranda, Emin Onur Karakaslar, Djamel Nehar-Belaid, Asa Thibodeau, Michael J Bale, Vinay K Kartha, Jim K Yee, Minh Y Mays, Chenyang Jiang, Andrew W Daman, Alexia Martinez de Paz, Dughan Ahimovic, Victor Ramos, Alexander Lercher, Erik Nielsen, Sergio Alvarez-Mulett, Ling Zheng, Andrew Earl, Alisha Yallowitz, Lexi Robbins, Elyse LaFond, Karissa L Weidman, Sabrina Racine-Brzostek, He S Yang, David R Price, Louise Leyre, André F Rendeiro, Hiranmayi Ravichandran, Junbum Kim, Alain C Borczuk, Charles M Rice, R Brad Jones, Edward J Schenck, Robert J Kaner, Amy Chadburn, Zhen Zhao, Virginia Pascual, Olivier Elemento, Robert E Schwartz, Jason D Buenrostro, Rachel E Niec, Franck J Barrat, Lindsay Lief, Joseph C Sun, Duygu Ucar, Steven Z Josefowicz.

  Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Keywords:  COVID-19; IL-6; PASC; epigenetic memory; epigenome; hematopoietic stem and progenitor cells; monocytes; peripheral blood mononuclear cell progenitor input enrichment; post-acute sequelae SARS-CoV-2 infection; single-cell; trained immunity; transcriptome

DOI:  https://doi.org/10.1016/j.cell.2023.07.019
Vaccines (Basel). 2023 Aug 01. pii: 1313. [Epub ahead of print]11(8):

Clinical and Experimental Determination of Protection Afforded by BCG Vaccination against Infection with Non-Tuberculous Mycobacteria: A Role in Cystic Fibrosis?

Sherridan Warner, Anneliese Blaxland, Claudio Counoupas, Janine Verstraete, Marco Zampoli, Ben J Marais, Dominic A Fitzgerald, Paul D Robinson, James A Triccas.

  Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4+ T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF.

Keywords:  BCG vaccination; Mycobacterium abscessus; cystic fibrosis; immune response; non-tuberculous mycobacteria

DOI:  https://doi.org/10.3390/vaccines11081313
Vaccines (Basel). 2023 Jul 28. pii: 1297. [Epub ahead of print]11(8):

Decreased Expression of CD314 by NK Cells Correlates with Their Ability to Respond by Producing IFN-γ after BCG Moscow Vaccination and Is Associated with Distinct Early Immune Responses.

Adeliane Castro da Costa, Lília Cristina de Souza Barbosa, André Kipnis, Ana Paula Junqueira-Kipnis.

  The immune response to vaccines is complex and results in various outcomes. BCG vaccination induces innate and specific responses that can lead to protection against tuberculosis, and cross-protection against other infections. NK cells have been associated with BCG-induced protection. Therefore, we hypothesize that differences in NK cell status before BCG vaccination may have a role in the ability of BCG to activate the immune response. Participants of a clinical trial were evaluated after BCG vaccination. The participants were assigned to different groups according to variation in IFN-γ expression by NK cells between days 1 and 15 after BCG vaccination. Individuals that presented a higher increase in IFN-γ expression by NK cells presented reduced CD314 expression at day 1, and after vaccination an increase in inflammatory NK cells and CD4 T-cell expression of IL-17. A negative correlation between expression of CD314 at day 1 and that of IFN-γ by NK cells after BCG vaccination was observed. Participants with lower of IFN-γ expression by NK cells after BCG vaccination presented an increase in the cytotoxic NK subpopulation and CD4 T-cell expression of IL-17 and IFN-γ. In conclusion, the expression of CD314 by NK cells before BCG vaccination influences their IFN-γ responses, generation of NK subpopulations, and the specific T immune response at 15 days after vaccination.

Keywords:  adaptive; heterogeneity response; innate immunity; neutrophil; tuberculosis; vaccine

DOI:  https://doi.org/10.3390/vaccines11081297
Methods Mol Biol. 2023 ;2700 93-116

Endotoxin-Tolerance Mimicking to Study TLR in Promotion of Tolerogenic DCs and Tr1 Cells.

Giulia Scalisi, Doriana Ricciuti, Giorgia Manni.

  Dendritic cells (DCs) are key regulators of immunogenic and tolerogenic immune responses. Both these immune responses require DCs respectively to activate effector T cells or to induce their anergy and T regulatory activity. Modifications of DCs in the laboratory and several pharmacological agents can enhance and stabilize their tolerogenic properties. Recent evidences demonstrate that activation of specific toll-like receptors (TLRs) can be involved in induction of DCs with tolerogenic properties able to initiate T regulatory cell responses.In the present chapter, we show a detail protocol to obtain in vitro regulatory conventional DCs (cDCs) in response to repeated exposure to lipopolysaccharide (LPS), a ligand of TLR4, by mimicking the mechanism of endotoxin tolerance. Subsequently, the protective effect of cDCs' conditionate with LPS will be describe in in vivo inflammatory model of endotoxemia. Finally, we illustrate the method to study the ability of LPS-conditionate cDCs to promote T regulatory cells in ex vivo system.

Keywords:  Bone marrow dendritic cells; Endotoxin tolerance; Immune tolerance; LPS; Toll-like receptors; Treg polarization

DOI:  https://doi.org/10.1007/978-1-0716-3366-3_5
Life Sci. 2023 Aug 18. pii: S0024-3205(23)00662-8. [Epub ahead of print]330 122027

Protective effect of β-glucan on Poly(I:C)-induced acute lung injury/inflammation: Therapeutic implications of viral infections in the respiratory system.

Satya Krishna Tirunavalli, Shashidhar Pramatha, Abhisheik Chowdary Eedara, Komal Paresh Walvekar, Christiana Immanuel, Pooja Potdar, Pawan G Nayak, Mallikarjuna Rao Chamallamudi, Ramakrishna Sistla, Sabarinadh Chilaka, Sai Balaji Andugulapati.

   AIMS: Acute lung inflammation, particularly acute respiratory distress syndrome (ARDS), is caused by a variety of pathogens including bacteria and viruses. β-Glucans have been reported to possess both anti-inflammatory and immunomodulatory properties. The current study evaluated the therapeutic effect of β-glucans on polyinosinic:polycytidylic acid (Poly(I:C)) induced lung inflammation in both hamster and mice models.
MAIN METHODS: Poly(I:C)-induced ALI/inflammation models were developed in hamsters (2.5 mg/kg) and mice (2 mg/kg) by delivering the Poly(I:C) intratracheally, and followed with and without β-glucan administration. After treatment, lung mechanics were assessed and lung tissues were isolated and analyzed for mRNA/protein expression, and histopathological examinations.
KEY FINDINGS: Poly(I:C) administration, caused a significant elevation of inflammatory marker's expression in lung tissues and showed abnormal lung mechanics in mice and hamsters. Interestingly, treatment with β-glucan significantly (p < 0.001) reversed the Poly(I:C)-induced inflammatory events and inflammatory markers expression in both mRNA (IL-6, IL-1β, TNF-α, CCL2 and CCL7) and protein levels (TNF-α, CD68, myeloperoxidase, neutrophil elastase, MUC-5Ac and iNOS). Lung functional assays revealed that β-glucan treatment significantly improved lung mechanics. Histopathological analysis showed that β-glucan treatment significantly attenuated the Poly(I:C) induced inflammatory cell infiltration, injury and goblet cell population in lung tissues. Consistent with these findings, β-glucan treatment markedly reduced the number of neutrophils and macrophages in lung tissues. Our findings further demonstrated that β-glucan could reduce inflammation by suppressing the MAPK pathway.
SIGNIFICANCE: These results suggested that β-glucan may attenuate the pathogenic effects of Poly(I:C)-induced ALI/ARDS via modulating the MAPK pathway, indicating β-glucan as a possible therapeutic agent for the treatment of viral-pulmonary inflammation/injury.

Keywords:  ARDS; Acute lung inflammation; Lung function evaluation; Poly(I:C); β-Glucan

DOI:  https://doi.org/10.1016/j.lfs.2023.122027
Nat Commun. 2023 Aug 22. 14(1): 5114

Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.

Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.

M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.

DOI: https://doi.org/10.1038/s41467-023-40738-4
Methods Mol Biol. 2023 ;2700 249-269

Study of Agonists of TLRs as Vaccine Adjuvants.

Francesca Mancini, Francesca Micoli, Omar Rossi.

  Vaccines adjuvants are critically needed to enhance the effectiveness of subunit vaccines. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists have received great attention as adjuvants in vaccines against severe and complex diseases such as cancer, AIDS, and malaria. Here, we describe in vitro assays, e.g., the Monocyte Activation Test, TLR-specific activation assay, and TLR-blocking experiments, used to assess TLR agonists adjuvanted vaccines' safety and to characterize their ability to stimulate the innate immunity. Such assays are physiologically relevant as they work with human cells and allow to overcome the complexity and variability related to in vivo assays.

Keywords:  Human cells; Safety; TLR activation; TLR agonists; Vaccines

DOI:  https://doi.org/10.1007/978-1-0716-3366-3_15
Hepatology. 2023 Aug 21.

Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.

Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano.

BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear.
APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3.
CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.

DOI: https://doi.org/10.1097/HEP.0000000000000568