bims-traimu 2022-11-20 papers

Issue of 2022–11–20
six papers selected by
Yantong Wan, Southern Medical University

JCI Insight. 2022 Nov 17. pii: e158183. [Epub ahead of print]

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress-mitochondrial ROS/glycolysis pathways.

Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L Williams, Chuanfu Li, Laisel Martinez, Roberto I Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, Xiaofeng Yang.

We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in non-liver tissues, whether TMAO promotes inflammation via trained immunity (TI) and made the following findings: Endoplasmic reticulum (ER) stress genes were co-upregulated with mitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas,;4) TMAO trans-differentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1; TMAO upregulated 3 mitochondrial genes and downregulated inflammation inhibitor DARS2, induced mitoROS; and mitoTEMPO inhibited TMAO-induced ICAM-1; and -glucan priming followed by TMAO re-stimulation upregulated TNF-α by inducing metabolic reprogramming; and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided novel insights over TMAO roles in inducing EC activation and innate immune trans-differentiation, inducing metabolic reprogramming and TI for enhanced vascular inflammation and new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammations, transplantation, aging, and cancers.

Keywords: Cardiovascular disease; Chronic kidney disease; Immunology; Inflammation; Innate immunity

DOI: https://doi.org/10.1172/jci.insight.158183

Shock. 2022 Nov 17.

Trained Immunity: A Potential Approach for Improving Host Immunity in Neonatal Sepsis.

Valerie E Polcz, Jaimar C Rincon, Russell B Hawkins, Evan L Barrios, Philip A Efron, Lyle L Moldawer, Shawn D Larson.

ABSTRACT: Sepsis, a dysregulated host immune response to infection, is one of the leading causes of neonatal mortality worldwide. Improved understanding of the perinatal immune system is critical to improve therapies to both term and preterm neonates at increased risk of sepsis. Our narrative outlines the known and unknown aspects of the human immune system through both the immune tolerant in utero period and the rapidly changing antigen-rich period after birth. We will highlight the key differences in innate and adaptive immunity noted through these developmental stages, and how the unique immune phenotype in early life contributes to the elevated risk of overwhelming infection and dysregulated immune responses to infection upon exposure to external antigens shortly after birth. Given an initial dependence on neonatal innate immune host responses, we will discuss the concept of innate immune memory, or "trained immunity", and describe several potential immune modulators which show promise in altering the dysregulated immune response in newborns and improving resilience to sepsis.

DOI: https://doi.org/10.1097/SHK.0000000000002054

Front Immunol. 2022 ;13 1059947

Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system.

Ling Zhao, Chen Hou, Naihong Yan.

Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.

Keywords: epigenetic modification; gut microbiome; innate immune; retinal inflammation; retinitis pigmentosa; trained immunity

DOI: https://doi.org/10.3389/fimmu.2022.1059947

Signal Transduct Target Ther. 2022 Nov 16. 7(1): 377

Innate immune imprints in SARS-CoV-2 Omicron variant infection convalescents.

SARS-CoV-2 Omicron variant infection generally gives rise to asymptomatic to moderate COVID-19 in vaccinated people. The immune cells can be reprogrammed or "imprinted" by vaccination and infections to generate protective immunity against subsequent challenges. Considering the immune imprint in Omicron infection is unclear, here we delineate the innate immune landscape of human Omicron infection via single-cell RNA sequencing, surface proteome profiling, and plasma cytokine quantification. We found that monocyte responses predominated in immune imprints of Omicron convalescents, with IL-1β-associated and interferon (IFN)-responsive signatures with mild and moderate symptoms, respectively. Low-density neutrophils increased and exhibited IL-1β-associated and IFN-responsive signatures similarly. Mild convalescents had increased blood IL-1β, CCL4, IL-9 levels and PI3+ neutrophils, indicating a bias to IL-1β responsiveness, while moderate convalescents had increased blood CXCL10 and IFN-responsive monocytes, suggesting durative IFN responses. Therefore, IL-1β- or IFN-responsiveness of myeloid cells may indicate the disease severity of Omicron infection and mediate post-COVID conditions.

DOI: https://doi.org/10.1038/s41392-022-01237-y

Nat Commun. 2022 Nov 15. 13(1): 6972

Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice.

Anneliese S Ashhurst, Matt D Johansen, Joshua W C Maxwell, Skye Stockdale, Caroline L Ashley, Anupriya Aggarwal, Rezwan Siddiquee, Stefan Miemczyk, Duc H Nguyen, Joel P Mackay, Claudio Counoupas, Scott N Byrne, Stuart Turville, Megan Steain, James A Triccas, Philip M Hansbro, Richard J Payne, Warwick J Britton.

Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam2Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4+ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam2Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.

DOI: https://doi.org/10.1038/s41467-022-34297-3

Immunobiology. 2022 Nov 02. pii: S0171-2985(22)00125-5. [Epub ahead of print]227(6): 152299

The Nurr7 agonist Cytosporone B differentially regulates inflammatory responses in human polarized macrophages.

Eduardo Patiño-Martínez, Miguel A Solís-Barbosa, Eduardo Santana, Erika González-Domínguez, Norma C Segovia-Gamboa, Marco A Meraz-Ríos, Emilio J Córdova, Jesús Valdés, Ángel L Corbí, Carmen Sánchez-Torres.

The orphan nuclear receptor Nur77 is involved in diverse cellular processes such as inflammation, proliferation, differentiation and survival. Stimuli like lipopolysaccharide (LPS) and tumor necrosis factor (TNF) increase Nur77 expression in human and murine macrophages, and it has been proposed that Nur77 plays a major role in dampening the inflammatory response. Here, we evaluated the expression and function of Nur77 in human anti-inflammatory and pro-inflammatory macrophages derived from blood monocytes cultured with macrophage colony-stimulating factor (M-MDMs) or granulocyte/macrophage colony-stimulating factor (GM-MDMs), respectively. Nur77 mRNA expression was significantly enhanced in M-MDMs compared with GM-MDMs, both constitutively and upon exposure to Toll-like receptor (TLR)2, 3, and 4 ligands. Nur77 activation with the agonist Cytosporone B (CsnB) significantly suppressed the production of TNF, interleukin (IL)-1β, IL-6, and IL-8 in GM-MDMs stimulated with LPS. In contrast, it tended to enhance the production of the anti-inflammatory cytokine IL-10. This effect was associated with reduced NF-κB p65 nuclear translocation. Similarly, Nur77 knockdown enhanced TNF production in GM-MDMs. CsnB effectively stimulated the transactivation activity of Nur77 in M-MDMs, but it did not alter cytokine synthesis or p65 nuclear translocation. However, Nur77 seemed to have a role in maintaining the anti-inflammatory profile of M-MDMs, since Nur77-deficient M-MDMs constitutively produced higher levels of TNF transcripts. Thus, in the absence of exogenous agonists, Nur77 activity favors the anti-inflammatory function of M-MDMs, whereas agonistic activation of this receptor preferentially drives attenuation of inflammation in inflammatory macrophages.

Keywords: Cytosporone B; Inflammatory response; Macrophage polarization; Nur77

DOI: https://doi.org/10.1016/j.imbio.2022.152299