bims-traimu 2022-07-17 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2022–07–17
eleven papers selected by
Yantong Wan, Southern Medical University

Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.
Maternal Prenatal Immunity, Neonatal Trained Immunity, and Early Airway Microbiota Shape Childhood Asthma Development.
Inflammatory memory and comorbidities.
Heterogeneous Nature of Trained Innate Immune Cells in Health and Disease.
Innate and Innate-like Effector Lymphocytes in Health and Disease.
Bacillus Calmette-Guérin in Immuno-Regulation of Alzheimer's Disease.
Questioning whether IgM Fc receptor (FcµR) is expressed by innate immune cells.
Human alveolar macrophages do not rely on glucose metabolism upon activation by lipopolysaccharide.
HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury.
CD47/SIRPα axis: bridging innate and adaptive immunity.
Inflammatory memory and tissue adaptation in sickness and in health.

J Inflamm Res. 2022 ;15 3829-3845

Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.

Huiting Zhou, Xiaying Lu, Jie Huang, Patrick Jordan, Shurong Ma, Lingqi Xu, Fangjie Hu, Huan Gui, He Zhao, Zhenjiang Bai, H Paul Redmond, Jiang Huai Wang, Jian Wang.

   Background: Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection.
Methods: This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates.
Results: Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity.
Conclusion: These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.

Keywords:  antimicrobial activity; epigenetic reprogramming; inflammatory response; intracellular metabolic rewiring; neonatal sepsis; trained immunity

DOI:  https://doi.org/10.2147/JIR.S363995
Allergy. 2022 Jul 16.

Maternal Prenatal Immunity, Neonatal Trained Immunity, and Early Airway Microbiota Shape Childhood Asthma Development.

Avery DeVries, Kathryn McCauley, Douglas Fadrosh, Kei E Fujimura, Debra A Stern, Susan V Lynch, Donata Vercelli.

   BACKGROUND: The path to childhood asthma is thought to initiate in utero and be further promoted by post-natal exposures. However, the underlying mechanisms remain underexplored. We hypothesized that prenatal maternal immune dysfunction associated with increased childhood asthma risk (revealed by low IFNγ:IL-13 secretion during the third trimester of pregnancy) alters neonatal immune training through epigenetic mechanisms and promotes early-life airway colonization by asthmagenic microbiota.
METHODS: We examined epigenetic, immunologic and microbial features potentially related to maternal prenatal immunity (IFNγ:IL-13 ratio) and childhood asthma in a birth cohort of mother/child dyads sampled pre-, peri-, and post-natally (N=155). Epigenome-wide DNA methylation and cytokine production were assessed in cord blood mononuclear cells (CMBC) by array profiling and ELISA, respectively. Nasopharyngeal microbiome composition was characterized at age 2-36 months by 16S rRNA sequencing.
RESULTS: Maternal prenatal immune status related to methylome profiles in neonates born to non-asthmatic mothers. A module of differentially methylated CpG sites enriched for microbe-responsive elements was associated with childhood asthma. In vitro responsiveness to microbial products was impaired in CBMCs from neonates born to mothers with the lowest IFN-γ:IL-13 ratio, suggesting defective neonatal innate immunity in those who developed asthma during childhood. These infants exhibited a distinct pattern of upper airway microbiota development characterized by early-life colonization by Haemophilus that transitioned to a Moraxella-dominated microbiota by age 36 months.
CONCLUSIONS: Maternal prenatal immune status shapes asthma development in her child by altering the epigenome and trained innate immunity at birth, and is associated with pathologic upper airway microbial colonization in early life.

Keywords:  DNA methylation; childhood asthma; maternal prenatal immunity; nasal microbiome; trained innate immunity

DOI:  https://doi.org/10.1111/all.15442
Clin Transl Med. 2022 Jul;12(7): e984

Inflammatory memory and comorbidities.

George Hajishengallis, Triantafyllos Chavakis.

DOI: https://doi.org/10.1002/ctm2.984
Hemasphere. 2022 Jul;6(7): e753

Heterogeneous Nature of Trained Innate Immune Cells in Health and Disease.

Francesca Vinchi, Muhammad Shahzad Ali.

DOI: https://doi.org/10.1097/HS9.0000000000000753
J Immunol. 2022 Jul 15. 209(2): 199-207

Innate and Innate-like Effector Lymphocytes in Health and Disease.

Luc Van Kaer, J Luke Postoak, Wenqiang Song, Lan Wu.

Lymphocytes can be functionally partitioned into subsets belonging to the innate or adaptive arms of the immune system. Subsets of innate and innate-like lymphocytes may or may not express Ag-specific receptors of the adaptive immune system, yet they are poised to respond with innate-like speed to pathogenic insults but lack the capacity to develop classical immunological memory. These lymphocyte subsets display a number of common properties that permit them to integrate danger and stress signals dispatched by innate sensor cells to facilitate the generation of specialized effector immune responses tailored toward specific pathogens or other insults. In this review, we discuss the functions of distinct subsets of innate and innate-like lymphocytes. A better understanding of the mechanisms by which these cells are activated in different contexts, their interactions with other immune cells, and their role in health and disease may inform the development of new or improved immunotherapies.

DOI: https://doi.org/10.4049/jimmunol.2200074
Front Aging Neurosci. 2022 ;14 861956

Bacillus Calmette-Guérin in Immuno-Regulation of Alzheimer's Disease.

Benjamin Y Klein, Charles L Greenblatt, Ofer N Gofrit, Hervé Bercovier.

  Bacillus Calmette-Guérin is frequently the treatment of choice of superficial bladder cancer. Exposing the urinary bladder of elderly patients with bladder cancer to the BCG vaccine reduced the risk of Alzheimer's disease (AD) substantially. Vaccines against other infectious microorganisms by other vaccination methods showed a similar but a lesser effect. This suggests that immune effects on AD are antigenically non-specific, likely being a metabolic result of immune system activation, similar to that shown for Juvenile diabetes. In this mini review we point to the benefit of BCG vaccine. We then briefly highlight the pathological involvement of the immune system in the AD both, in the peripheral and the central (brain) compartments. Given the uncertain prophylactic mechanism of the BCG effect against AD we propose to take advantage of the therapeutically planned bladder exposure to BCG. Based on pathological aggregation of wrongly cleaved amyloid precursor protein (APP) resistant to the unfolded protein response (UPR) which results in amyloid beta plaques we predict that BCG may impact the UPR signaling cascade. In addition pathways of innate immunity training concerned with energy metabolism, predict capability of activated immune cells to substitute deranged astrocytes that fail to support neuronal energy metabolism. This mini review points to ways through which immune cells can mediate between BCG vaccination and AD to support the wellness of the central nervous system.

Keywords:  Alzheimer’s disease; BCG; immunometabolism; intravesical; vaccination

DOI:  https://doi.org/10.3389/fnagi.2022.861956
Nat Commun. 2022 Jul 11. 13(1): 3951

Questioning whether IgM Fc receptor (FcµR) is expressed by innate immune cells.

Christopher M Skopnik, René Riedel, Richard K Addo, Gitta Anne Heinz, Frederik Heinrich, Kazuhito Honjo, Pawel Durek, Philipp Enghard, Mir-Farzin Mashreghi, Andreas Radbruch, Hiromi Kubagawa.

DOI: https://doi.org/10.1038/s41467-022-29407-0
Biochim Biophys Acta Mol Basis Dis. 2022 Jul 11. pii: S0925-4439(22)00159-4. [Epub ahead of print] 166488

Human alveolar macrophages do not rely on glucose metabolism upon activation by lipopolysaccharide.

Liza Pereverzeva, Christine C A van Linge, Alex R Schuurman, Augustijn M Klarenbeek, Ivan Ramirez Moral, Natasja A Otto, Hessel Peters Sengers, Joe M Butler, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, W Joost Wiersinga, Peter I Bonta, Jouke T Annema, Alex F de Vos, Tom van der Poll.

  Most macrophages generate energy to mount an inflammatory cytokine response by increased glucose metabolism through intracellular glycolysis. Previous studies have suggested that alveolar macrophages (AMs), which reside in a glucose-poor natural environment, are less capable to utilize glycolysis and instead rely on other substrates to fuel oxidative phosphorylation (OXPHOS) for energy supply. At present, it is not known whether AMs are capable to use glucose metabolism to produce cytokines when other metabolic options are blocked. Here, we studied human AMs retrieved by bronchoalveolar lavage from healthy subjects, and examined their glucose metabolism in response to activation by the gram-negative bacterial component lipopolysaccharide (LPS) ex vivo. The immunological and metabolic responses of AMs were compared to those of cultured blood monocyte-derived macrophages (MDMs) from the same subjects. LPS stimulation enhanced cytokine release by both AMs and MDMs, which was associated with increased lactate release by MDMs (reflecting glycolysis), but not by AMs. In agreement, LPS induced higher mRNA expression of multiple glycolytic regulators in MDMs, but not in AMs. Flux analyses of [13C]-glucose revealed no differences in [13C]-incorporation in glucose metabolism intermediates in AMs. Inhibition of OXPHOS by oligomycin strongly reduced LPS-induced cytokine production by AMs, but not by MDMs. Collectively, these results indicate that human AMs, in contrast to MDMs, do not use glucose metabolism during LPS-induced activation and fully rely on OXPHOS for cytokine production.

Keywords:  Alveolar macrophages; Glucose metabolism; Lipopolysaccharide; Monocyte-derived macrophages

DOI:  https://doi.org/10.1016/j.bbadis.2022.166488
Elife. 2022 Jul 13. pii: e77457. [Epub ahead of print]11

HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury.

Parker S Woods, Lucas M Kimmig, Kaitlyn A Sun, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Rengül Cetin-Atalay, Willard W Sharp, Robert B Hamanaka, Gökhan M Mutlu.

  Cellular metabolism is a critical regulator of macrophage effector function. Tissue-resident alveolar macrophages (TR-AMs) inhabit a unique niche marked by high oxygen and low glucose. We have recently shown that in contrast to bone marrow-derived macrophages (BMDMs), TR-AMs do not utilize glycolysis and instead predominantly rely on mitochondrial function for their effector response. It is not known how changes in local oxygen concentration that occur during conditions such as acute respiratory distress syndrome (ARDS) might affect TR-AM metabolism and function; however, ARDS is associated with progressive loss of TR-AMs, which correlates with the severity of disease and mortality. Here, we demonstrate that hypoxia robustly stabilizes HIF-1α in TR-AMs to promote a glycolytic phenotype. Hypoxia altered TR-AM metabolite signatures, cytokine production, and decreased their sensitivity to the inhibition of mitochondrial function. By contrast, hypoxia had minimal effects on BMDM metabolism. The effects of hypoxia on TR-AMs were mimicked by FG-4592, a HIF-1α stabilizer. Treatment with FG-4592 decreased TR-AM death and attenuated acute lung injury in mice. These findings reveal the importance of microenvironment in determining macrophage metabolic phenotype, and highlight the therapeutic potential in targeting cellular metabolism to improve outcomes in diseases characterized by acute inflammation.

Keywords:  cell biology; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.77457
J Immunother Cancer. 2022 Jul;pii: e004589. [Epub ahead of print]10(7):

CD47/SIRPα axis: bridging innate and adaptive immunity.

Anneloes van Duijn, Sjoerd H Van der Burg, Ferenc A Scheeren.

  Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) axis. The SIRPα receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a 'don't eat me' signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRPα have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRPα axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRPα axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRPα axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRPα axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRPα immune checkpoint therapy.

Keywords:  adaptive immunity; immunity, innate; immunotherapy; macrophages; phagocytosis

DOI:  https://doi.org/10.1136/jitc-2022-004589
Nature. 2022 Jul;607(7918): 249-255

Inflammatory memory and tissue adaptation in sickness and in health.

Shruti Naik, Elaine Fuchs.

Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege of the immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences-good and bad-of these epigenetic memories and their implications for human health and disease.

DOI: https://doi.org/10.1038/s41586-022-04919-3