Bacterial infections, particularly Salmonella, pose a significant health risk to neonates due to their underdeveloped immune systems. Understanding the immune responses in the neonatal intestine during S. Typhimurium infection is crucial for developing effective therapeutic and prevention strategies. This study found neonatal rats exhibited severe symptoms, including significant mortality, body weight loss, diarrhea, and bacterial load increases in the gastrointestinal tract and various organs, particularly in the ileum. Moreover, neonatal rats exhibited a high percentage of type 3 immune cells including Th17, γδT17, and ILC3 after S. Typhimurium infection. Furthermore, cintirorgon treatment during early life, the agonist of RORγt, significantly enhanced IL-17A-secreting type 3 immune response and alleviated the symptoms. Our data reveal targeting RORγt and IL-17A pathways may offer a promising therapeutic strategy for bacterial infections in neonatal populations.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Stem cell engraftment is currently a promising approach for type 1 diabetes mellitus (T1DM) treatment. In our previous study, engraftment of a combination of human amniotic epithelial cells (hAECs) and hyaluronic acid (HA) showed potent anti-diabetic effect in streptozotocin (STZ)-induced T1DM mice via tail vein injection. Here, we adopted a different route of stem cell delivery, that is via pancreatic subcapsular transplantation. This combined local engraftment of hAECs and HA in STZ-induced T1DM rats showed potent anti-diabetic activity, leading to stronger hypoglycaemia, more intact islet structure and increased number of insulin-positive cells compared with those with hAECs or insulin treatments. Engraftment of hAECs alone increased the proportion of Th1 and T-reg cells and decreased the proportion of Th2 and Th17 cells to protect islet β cells in STZ-induced T1DM rats, whereas the combined engraftment of hAECs and HA showed more potent regulatory capacity, considerably decreased the level of TNF-α and IL-17 and increased the level of TGF-β1 compared with those by other treatments. The potent synergistic effect of HA contributed to the recovery of immune balance in the diabetic rat model, thereby suggesting a new strategy for effective treatment of T1DM.
© 2023 The Scandinavian Foundation for Immunology.

T lymphocyte and macrophage infiltration in the aortic wall is critical for abdominal aortic aneurysm (AAA). However, how T lymphocytes interact with macrophages in the pathogenesis of AAA remains largely uncharacterized. In an elastase-induced murine AAA model, we first found that the expression of pyruvate kinase muscle isozyme 2 (PKM2), the last rate-limiting enzyme in glycolysis, was increased in infiltrated T lymphocytes of vascular lesions. T lymphocyte-specific PKM2 deficiency in mice (LckCrePKM2fl/fl) or intraperitoneal administration of the sphingomyelinase inhibitor GW4869 caused a significant attenuation of the elastase-increased aortic diameter, AAA incidence, elastic fiber disruption, matrix metalloproteinases (MMPs) expression, and macrophage infiltration in the vascular adventitia compared with those in PKM2fl/fl mice. Mechanistically, extracellular vesicles (EVs) derived from PKM2-activated T lymphocytes elevated macrophage iron accumulation, lipid peroxidation, and migration in vitro, while macrophages treated with EVs from PKM2-null T lymphocytes or pretreated with the lipid peroxidation inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), or the iron chelating agent deferoxamine mesylate (DFOM) reversed these effects. In vascular lesions of elastase-induced LckCrePKM2fl/fl mice with AAA, the oxidant system weakened, with downregulated 4-hydroxynonenal (4-HNE) levels and strengthened antioxidant defense systems with upregulated glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (Slc7a11) expressions in macrophages. High-throughput metabolomics showed that EVs derived from PKM2-activated T lymphocytes contained increased levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, which may provide abundant substrates for lipid peroxidation in target macrophages. More importantly, upregulated T lymphocyte PKM2 expression was also found in clinical AAA subjects, and EVs isolated from AAA patient plasma enhanced macrophage iron accumulation, lipid peroxidation, and migration ex vivo. Therefore, from cell-cell crosstalk and metabolic perspectives, the present study shows that PKM2-activated T lymphocyte-derived EVs may drive AAA progression by promoting macrophage redox imbalance and migration, and targeting the T lymphocyte-EV-macrophage axis may be a potential strategy for early warning and treating AAA.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that would permanently damage the affected joints. Unfortunately, a large proportion of RA patients fail to respond adequately to current treatments. Here, repurposing hemin and its ultra-long-acting formulation were explored for the effective treatment of RA in animal models. We provided evidence that hemin prevented the onset and ameliorated the clinical course of RA. Notably, hemin treatment rescued the dysregulated gene expression in animal models of RA, resulting in attenuation of Th1/Th17 cell-mediated responses and proinflammatory cytokines. Moreover, we further formulated hemin into the in-situ forming implant, and a single injection of the ultra-long-acting hemin exerted potent disease-modifying effects for at least six weeks with a remarkable dose reduction. Taken together, given the potent anti-inflammatory and immunosuppressive effects, the once-monthly hemin injection holds promise for rapid clinical translation, and represents a potential strategy to treat RA and possibly other autoimmune diseases.
© 2021 The Authors.