bims-traimu 2023-03-19 papers

Issue of 2023–03–19
six papers selected by
Yantong Wan, Southern Medical University

Allergy. 2023 Mar 16.

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma.

Hesam Movassagh, Mary Prunicki, Abhinav Kaushik, Xiaoying Zhou, Diane Dunham, Eric M Smith, Ziyuan He, German R Aleman Muench, Minyi Shi, Annika K Weimer, Shu Cao, Sandra Andorf, Amir Feizi, Michael P Snyder, Pejman Soroosh, Elizabeth D Mellins, Kari C Nadeau.

BACKGROUND: The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma, are not well understood. We investigated whether ambient levels of fine PM with aerodynamic diameter ≤2.5 microns (PM2.5 ) are associated with alterations in circulating monocytes in children with or without asthma.
METHODS: Monocyte phenotyping was performed by cytometry time-of-flight (CyTOF). Cytokines were measured using cytomtric bead array and Luminex assay. ChIP-Seq was utilized to address histone modifications in monocytes.
RESULTS: Increased exposure to ambient PM2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by the upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or lipopolysaccharide. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes.
CONCLUSION: The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

Keywords: asthma; innate immunity; pediatrics

DOI: https://doi.org/10.1111/all.15692

Signal Transduct Target Ther. 2023 Mar 11. 8(1): 110

Activation of immune signals during organ transplantation.

Qingwen Li, Peixiang Lan.

The activation of host's innate and adaptive immune systems can lead to acute and chronic graft rejection, which seriously impacts graft survival. Thus, it is particularly significant to clarify the immune signals, which are critical to the initiation and maintenance of rejection generated after transplantation. The initiation of response to graft is dependent on sensing of danger and stranger molecules. The ischemia and reperfusion of grafts lead to cell stress or death, followed by releasing a variety of damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs) of host immune cells to activate intracellular immune signals and induce sterile inflammation. In addition to DAMPs, the graft exposed to 'non-self' antigens (stranger molecules) are recognized by the host immune system, stimulating a more intense immune response and further aggravating the graft damage. The polymorphism of MHC genes between different individuals is the key for host or donor immune cells to identify heterologous 'non-self' components in allogeneic and xenogeneic organ transplantation. The recognition of 'non-self' antigen by immune cells mediates the activation of immune signals between donor and host, resulting in adaptive memory immunity and innate trained immunity to the graft, which poses a challenge to the long-term survival of the graft. This review focuses on innate and adaptive immune cells receptor recognition of damage-associated molecular patterns, alloantigens and xenoantigens, which is described as danger model and stranger model. In this review, we also discuss the innate trained immunity in organ transplantation.

DOI: https://doi.org/10.1038/s41392-023-01377-9

Microbiol Spectr. 2023 Mar 14. e0503522

Oral Administration of Universal Bacterium-Vectored Nucleocapsid-Expressing COVID-19 Vaccine is Efficacious in Hamsters.

Qingmei Jia, Helle Bielefeldt-Ohmann, Rachel M Maison, Airn Hartwig, Saša Masleša-Galić, Richard A Bowen, Marcus A Horwitz.

Oral delivery of an inexpensive COVID-19 (coronavirus disease 2019) vaccine could dramatically improve immunization rates, especially in low- and middle-income countries. Previously, we described a potential universal COVID-19 vaccine, rLVS ΔcapB/MN, comprising a replicating bacterial vector, LVS (live vaccine strain) ΔcapB, expressing the highly conserved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) membrane and nucleocapsid (N) proteins, which, when administered intradermally or intranasally, protects hamsters from severe COVID-19-like disease after high-dose SARS-CoV-2 respiratory challenge. Here, we show that oral administration of the vaccine also protects against high-dose SARS-CoV-2 respiratory challenge; its protection is comparable to that of intradermal, intranasal, or subcutaneous administration. Hamsters were protected against severe weight loss and lung pathology and had reduced oropharyngeal and lung virus titers. Protection against weight loss and histopathology by the vaccine, which in mice induces splenic and lung cell interferon gamma in response to N protein stimulation, was correlated in hamsters with pre-challenge serum anti-N TH1-biased IgG (IgG2/3). Thus, rLVS ΔcapB/MN has potential as an oral universal COVID-19 vaccine. IMPORTANCE The COVID-19 pandemic continues to rage into its fourth year worldwide. To protect the world's population most effectively from severe disease, hospitalization, and death, a vaccine is needed that is resistant to rapidly emerging viral variants of the causative agent SARS-CoV-2, inexpensive to manufacture, store, and transport, and easy to administer. Ideally, such a vaccine would be capable of oral administration, especially in resource-poor countries of the world where there are shortages of needles, syringes and trained personnel to administer injectable vaccines. Here, we show that oral administration of a bacterium-vectored vaccine meeting all these criteria protects naturally susceptible Syrian hamsters from severe COVID-19-like disease, including severe weight loss and lung pathology, after high-dose SARS-CoV-2 respiratory challenge. As the vaccine is based upon inducing immunity to highly conserved SARS-CoV-2 membrane and nucleocapsid proteins, as opposed to the rapidly mutating Spike protein, it should remain resistant to newly emerging SARS-CoV-2 variants.

Keywords: COVID-19; SARS-CoV-2; Syrian hamster; bacterial vector; membrane protein; mouse; nucleocapsid protein; oral administration; oral vaccine; single vector platform; single vector platform vaccine; vaccine; vaccine vector

DOI: https://doi.org/10.1128/spectrum.05035-22

Front Immunol. 2023 ;14 1135223

Single-cell analysis reveals TLR-induced macrophage heterogeneity and quorum sensing dictate population wide anti-inflammatory feedback in response to LPS.

Bart M Tiemeijer, Sebastiaan Heester, Ashley Y W Sturtewagen, Anthal I P M Smits, Jurjen Tel.

The role of macrophages in controlling tissue inflammation is indispensable to ensure a context-appropriate response to pathogens whilst preventing excessive tissue damage. Their initial response is largely characterized by high production of tumor necrosis factor alpha (TNFα) which primes and attracts other immune cells, thereafter, followed by production of interleukin 10 (IL-10) which inhibits cell activation and steers towards resolving of inflammation. This delicate balance is understood at a population level but how it is initiated at a single-cell level remains elusive. Here, we utilize our previously developed droplet approach to probe single-cell macrophage activation in response to toll-like receptor 4 (TLR4) stimulation, and how single-cell heterogeneity and cellular communication affect macrophage-mediated inflammatory homeostasis. We show that only a fraction of macrophages can produce IL-10 in addition to TNFα upon LPS-induced activation, and that these cells are not phenotypically different from IL-10 non-producers nor exhibit a distinct transcriptional pathway. Finally, we demonstrate that the dynamics of TNFα and IL-10 are heavily controlled by macrophage density as evidenced by 3D hydrogel cultures suggesting a potential role for quorum sensing. These exploratory results emphasize the relevance of understanding the complex communication between macrophages and other immune cells and how these amount to population-wide responses.

Keywords: IL-10; TLR4; heterogeneity; macrophage; single-cell

DOI: https://doi.org/10.3389/fimmu.2023.1135223

Mol Med. 2023 Mar 14. 29(1): 31

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

Sunyue He, Yuchen Zhao, Guoxing Wang, Qiaofang Ke, Nan Wu, Lusi Lu, Jiahua Wu, Shuiya Sun, Weihua Jin, Wenjing Zhang, Jiaqiang Zhou.

BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming.
METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment.
RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment.
CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Keywords: 4-Octyl itaconate; Islet injury; Macrophage activation; Type 1 diabetes

DOI: https://doi.org/10.1186/s10020-023-00626-5