bims-bac4me 2023-04-09 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023‒04‒09
nine papers selected by
Chun-Chi Chang
University Hospital Zurich

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome.
Trained immunity from the perspective of Plasmodium Infection.
Lactobacillus paracasei CNCM I-5220-derived postbiotic protects from the leaky-gut.
Long-term tolerance to skin commensals is established neonatally through a specialized dendritic cell subgroup.
A flagellin-conjugate protein induces dual NLRC4- and NLRP3-inflammasome activation which modulates inflammatory cytokine secretion from macrophages.
Fucosylated TLR4 mediates communication between mutualist fucotrophic microbiota and mammalian gut mucosa.
Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.
Establishment of a human microbiome- and immune system-reconstituted dual-humanized mouse model.
Dissecting skin microbiota and microenvironment for the development of therapeutic strategies.

Front Immunol. 2023 ;14 1117548

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome.

Lian Wang, Dongguang Wang, Tianli Zhang, Yao Ma, Xiang Tong, Hong Fan.

  Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.

Keywords:  acute lung injury; acute respiratory distress syndrome; immunometabolism; macrophage polarization; metabolic reprogramming; polarization regulation

DOI:  https://doi.org/10.3389/fimmu.2023.1117548
Eur J Immunol. 2023 Apr 05. e2250268

Trained immunity from the perspective of Plasmodium Infection.

Jiajie Li, Lin Liu, Dianhui Chen, Weiguo Yin, Jun Huang.

  The immune system of vertebrates includes innate immunity and adaptive immunity, and the network between them enables the host to fight against invasions of various pathogens. Recently, studies discovered that immune memory is one of the features of innate immunity, breaking the previous opinion that immune memory exists only in adaptive immunity. Immune memory supports innate immune cells to respond efficiently upon reinfection or restimulation. During the Plasmodium infection, the innate immune system is the first to be triggered, and innate immune cells are activated by components from Plasmodium or Plasmodium-infected red blood cells. Innate immune cells could be induced to develop memory after the activation and may play an important role in the subsequent infection of Plasmodium or other pathogens and stimulation. This review will discuss the recent findings relevant to trained immunity and Plasmodium infection, facilitating the understanding of the role of trained immunity in malaria and other diseases and the development of therapeutic strategies based on trained immunity. This article is protected by copyright. All rights reserved.

Keywords:  immune memory; innate immunity; malaria; plasmodium; trained immunity

DOI:  https://doi.org/10.1002/eji.202250268
Front Microbiol. 2023 ;14 1157164

Lactobacillus paracasei CNCM I-5220-derived postbiotic protects from the leaky-gut.

Francesca Algieri, Nina Tanaskovic, Cindy Cardenas Rincon, Elisabetta Notario, Daniele Braga, Graziano Pesole, Roberto Rusconi, Giuseppe Penna, Maria Rescigno.

  The maintenance of intestinal barrier function is essential for preventing different pathologies, such as the leaky gut syndrome (LGS), which is characterized by the passage of harmful agents, like bacteria, toxins, and viruses, into the bloodstream. Intestinal barrier integrity is controlled by several players, including the gut microbiota. Various molecules, called postbiotics, are released during the natural metabolic activity of the microbiota. Postbiotics can regulate host-microbe interactions, epithelial homeostasis, and have overall benefits for our health. In this work, we used in vitro and in vivo systems to demonstrate the role of Lactobacillus paracasei CNCM I-5220-derived postbiotic (LP-PBF) in preserving intestinal barrier integrity. We demonstrated in vitro that LP-PBF restored the morphology of tight junctions (TJs) that were altered upon Salmonella typhimurium exposure. In vivo, LP-PBF protected the gut vascular barrier and blocked S. typhimurium dissemination into the bloodstream. Interestingly, we found that LP-PBF interacts not only with the host cells, but also directly with S. typhimurium blocking its biofilm formation, partially due to the presence of biosurfactants. This study highlights that LP-PBF is beneficial in maintaining gut homeostasis due to the synergistic effect of its different components. These results suggest that LP-PBF could be utilized in managing several pathologies displaying an impaired intestinal barrier function.

Keywords:  Lactobacillus paracasei; Salmonella typhimurium; epithelial barrier integrity; gut vascular barrier; leaky-gut; microbiota; postbiotic; tight junction

DOI:  https://doi.org/10.3389/fmicb.2023.1157164
Immunity. 2023 Mar 29. pii: S1074-7613(23)00128-0. [Epub ahead of print]

Long-term tolerance to skin commensals is established neonatally through a specialized dendritic cell subgroup.

Antonin Weckel, Miqdad O Dhariwala, Kevin Ly, Victoria M Tran, Oluwasunmisola T Ojewumi, Julianne B Riggs, Jeanmarie R Gonzalez, Laura R Dwyer, Joy N Okoro, John M Leech, Margot S Bacino, Grace D Cho, Geil Merana, Niroshana Anandasabapathy, Yosuke Kumamoto, Tiffany C Scharschmidt.

  Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a specialized subset of antigen-presenting cells. More particularly, CD301b+ type 2 conventional dendritic cells (DCs) in neonatal skin were specifically capable of uptake and presentation of commensal antigens for the generation of regulatory T (Treg) cells. CD301b+ DC2 were enriched for phagocytosis and maturation programs, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early-life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic-acid-producing enzyme, RALDH2, the deletion of which limited commensal-specific Treg cell generation. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early-life tolerance at the cutaneous interface.

Keywords:  Staphylococcus epidermidis; commensal bacteria; commensals; dendritic cells; early-life immunity; neonatal immunity; regulatory T cells; retinoic acid; skin; tolerance

DOI:  https://doi.org/10.1016/j.immuni.2023.03.008
Front Immunol. 2023 ;14 1136669

A flagellin-conjugate protein induces dual NLRC4- and NLRP3-inflammasome activation which modulates inflammatory cytokine secretion from macrophages.

Yen-Ju Lin, Annette Jamin, Sonja Wolfheimer, Anna Fiedler, Ann-Christine Junker, Alexandra Goretzki, Stephan Scheurer, Stefan Schülke.

  Background: A recombinant fusion protein combining the adjuvant and TLR5-ligand flagellin with the major birch pollen allergen Bet v 1 (rFlaA:Betv1) has been suggested to prevent the manifestation of birch allergy. Noteworthy, rFlaA:Betv1 induced both pro- and anti-inflammatory responses which were differentially regulated. However, the mechanism by which flagellin fusion proteins modulate allergen-specific immune responses, especially the mechanisms underlying IL-1β secretion and their contribution to the overall immune responses remains elusive.Objective: To investigate the mechanisms underlying the production of IL-1β from rFlaA:Betv1 stimulated macrophages.
Methods: Macrophages were derived from mouse peritoneal-, human buffy-coat-, and PMA-differentiated THP-1 (wild type or lacking either ASC, NLRP3, or NLRC4) cells. Macrophages were stimulated with non-modified rFlaA:Betv1, mutant variants lacking either the flagellin DC0 domain or a sequence motif formerly described to mediate TLR5-activation, and respective controls in the presence or absence of inhibitors interfering with MAPK- and NFκB-signaling. Cytokine secretion was analyzed by ELISA and intracellular signaling by Western Blot. To study the contribution of IL-1β to the overall immune responses, IL1R-deficient mouse peritoneal macrophages were used.
Results: rFlaA:Betv1 consistently activated all types of investigated macrophages, inducing higher IL-1β secretion compared with the equimolar mixture of both proteins. rFlaA:Betv1-induced activation of THP-1 macrophages was shown to be independent of either the TLR5-activating sequence motif or the flagellin DC0 domain but depended on both NLRP3- and NLRC4-inflammasomes. In addition, NFκB and SAP/JNK MAP kinases regulated rFlaA:Betv1-induced inflammasome activation and cytokine secretion by modulating pro-Caspase-1- and pro-IL-1β-expression in THP-1 macrophages. Finally, lack of IL-1β positive feedback via the IL1R strongly diminished the rFlaA:Betv1-induced secretion of IL-1β, IL-6, and TNF-α from peritoneal macrophages.
Conclusion: The mechanisms contributing to rFlaA:Betv1-induced IL-1β secretion from macrophages were shown to be complex, involving both NLRC4- and NLRP3-inflammsomes, as well as NFκB- and SAP/JNK MAP kinase-signaling. Better understanding the mechanisms regulating the activation of immune cells by novel therapeutic candidates like the rFlaA:Betv1 fusion protein will allow us to further improve and develop new treatment strategies when using flagellin as an adjuvant.

Keywords:  NLRC4; NLRP3; flagellin fusion protein; inflammasome; macrophage

DOI:  https://doi.org/10.3389/fimmu.2023.1136669
Front Med (Lausanne). 2023 ;10 1070734

Fucosylated TLR4 mediates communication between mutualist fucotrophic microbiota and mammalian gut mucosa.

Nanda N Nanthakumar, Di Meng, David S Newburg.

  Objective: The glycans on the mucosa of suckling mice are predominantly sialylated; upon weaning, fucosylated glycans preponderate. This manifestation of mutualism between fucotrophic bacteria and the mature host utilizes a sentinel receptor in the intestinal mucosa; this receptor was isolated to distinguish its structural and functional features.Design: Provisional identification of the sentinel gut receptor as fuc-TLR4 was through colonization of germ-free mutant mice. Conventional mice whose microbiota was depleted with a cocktail of antibiotics were used to further define the nature and functions of fuc-TLR4 sentinel, and to define the role of the fucotrophic microbiota in gut homeostasis and recovery from insult. The nature of the sentinel was confirmed in cultured human HEL cells.
Results: Fuc-TLR4 activity is distinct from that of TLR4. Activated mucosal fuc-TLR4 induces a fuc-TLR4 dependent non-inflammatory (ERK and JNK dependent, NF-κB independent) signaling cascade, initiating induction of fucosyltransferase 2 (secretor) gene transcription. In vitro, either defucosylation or TLR4 knockdown abrogates FUT2 induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. In vivo, fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury in vivo.
Conclusion: In mature mice, fucosyl-TLR4 mediated gut fucosylation creates a niche that supports the healthy fucose-dependent mutualism between the mammalian gut and its fucotrophic microbes. Such microbiota-induced Fuc-TLR4 signaling supports initial colonization of the secretor gut, recovery from dysbiosis, and restoration or preservation of intestinal homeostasis.

Keywords:  Toll-like receptor 4; cell signaling; fusosylated TLR4; fut2 secretor gene; intestinal mucosa and intestinal microbiota; microbiota; mutualist fucotropic bacteria; transkingdom communication

DOI:  https://doi.org/10.3389/fmed.2023.1070734
Immunity. 2023 Mar 26. pii: S1074-7613(23)00119-X. [Epub ahead of print]

Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.

Md Al Amin Sikder, Ridwan B Rashid, Tufael Ahmed, Ismail Sebina, Daniel R Howard, Md Ashik Ullah, Muhammed Mahfuzur Rahman, Jason P Lynch, Bodie Curren, Rhiannon B Werder, Jennifer Simpson, Alec Bissell, Mark Morrison, Carina Walpole, Kristen J Radford, Vinod Kumar, Trent M Woodruff, Tan Hui Ying, Ayesha Ali, Gerard E Kaiko, John W Upham, Robert D Hoelzle, Páraic Ó Cuív, Patrick G Holt, Paul G Dennis, Simon Phipps.

  Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs.

Keywords:  Flt3L; acute lower respiratory tract infection; asthma; bronchiolitis; dendritic cells; microbiome; milk; regulatory T cell; respiratory synctial virus; virus

DOI:  https://doi.org/10.1016/j.immuni.2023.03.002
Exp Anim. 2023 Apr 04.

Establishment of a human microbiome- and immune system-reconstituted dual-humanized mouse model.

Yuyo Ka, Ryoji Ito, Ryoko Nozu, Kayo Tomiyama, Masami Ueno, Tomoyuki Ogura, Riichi Takahashi.

  Humanized mice are widely used to study the human immune system in vivo and investigate therapeutic targets for various human diseases. Immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice transferred with human hematopoietic stem cells are a useful model for studying human immune systems and analyzing engrafted human immune cells. The gut microbiota plays a significant role in the development and function of immune cells and the maintenance of immune homeostasis; however, there is currently no available animal model that has been reconstituted with human gut microbiota and immune systems in vivo. In this study, we established a new model of CD34+ cell-transferred humanized germ-free NOG mice using an aseptic method. Flow cytometric analysis revealed that the germ-free humanized mice exhibited a lower level of human CD3+ T cells than the SPF humanized mice. Additionally, we found that the human CD3+ T cells slightly increased after transplanting human gut microbiota into the germ-free humanized mice, suggesting that the human microbiota supports T cell proliferation or maintenance in humanized mice colonized by the gut microbiota. Consequently, the dual-humanized mice may be useful for investigating the physiological role of the gut microbiota in human immunity in vivo and for application as a new humanized mouse model in cancer immunology.

Keywords:  CD34+ cells; NOG mice; fecal microbiota transplantation; germ-free; humanized mice

DOI:  https://doi.org/10.1538/expanim.23-0025
Curr Opin Microbiol. 2023 Apr 03. pii: S1369-5274(23)00048-6. [Epub ahead of print]74 102311

Dissecting skin microbiota and microenvironment for the development of therapeutic strategies.

Yoshihiro Ito, Masayuki Amagai.

The skin is a pivotal barrier between the human body and the environment, and is a habitat for numerous microorganisms. While host-microbiota interactions in the skin are essential for homeostasis, disturbances in microbial composition and the abnormal growth of certain bacteria are associated with various diseases. Here, we identify strains and communities of skin commensals that contribute to or impair skin barrier function. Furthermore, we discuss the skin microenvironments suitable for specific microbiota that exert therapeutic effects and suggest focus areas for the prospective development of therapeutic strategies using bacterial agents. Finally, we highlight recent efforts to treat skin diseases associated with live bacteria.

DOI: https://doi.org/10.1016/j.mib.2023.102311