Atherosclerosis (AS) is an inflammatory disease involving multiple factors in its initiation and development. In recent years, the potential application of mesenchymal stem cells (MSCs) for treating AS has been investigated. This study examined the effect of TNF-α preconditioning on MSCs' therapeutic efficacy in treating AS in ApoE KO mice. TNF-α-treated MSCs were administered to high-fat diet-treated ApoE KO mice. Cytokine and serum lipid levels were measured before and after treatment. Cryosections of the atherosclerotic aorta were stained with Oil-Red-O, and the relative areas of atherosclerotic lesions were measured. The level of Tregs were increased in TNF-α-MSC-treated animals compared to the MSCs group. In addition, the systemic administration of TNF-α-MSCs to ApoE KO mice reduced the level of proinflammatory cytokines such as TNF-α and IFN-γ and increased the level of the immunosuppressive IL-10 in the blood serum. Total cholesterol and LDL levels were decreased, and HDL levels were increased in the TNF-α-MSCs group of ApoE KO mice. A histological analysis showed that TNF-α-MSCs decreased the size of the atherosclerotic lesion in the aorta of ApoE KO mice by 38%, although there was no significant difference when compared with untreated MSCs. Thus, our data demonstrate that TNF-α-MSCs are more effective at treating AS than untreated MSCs.

Terminally differentiated keratinocytes are critical for epidermal function and are surrounded by involucrin (IVL). Increased IVL expression is associated with a near-selective sweep in European populations compared with those in Africa. This positive selection for increased IVL in the epidermis identifies human adaptation outside of Africa. The functional significance is unclear. We hypothesize that IVL modulates the environmentally sensitive vitamin D receptor (VDR) in the epidermis. We investigated VDR activity in Ivl‒/‒ and wild-type mice using vitamin D agonist (MC903) treatment and comprehensively determined the inflammatory response using single-cell RNA sequencing and associated skin microbiome changes using 16S bacterial phylotyping. VDR activity and target gene expression were reduced in Ivl‒/‒ mouse skin, with decreased MC903-mediated skin inflammation and significant reductions in CD4+ T cells, basophils, macrophages, monocytes, and type II basal keratinocytes and an increase in suprabasal keratinocytes. Coinciding with the dampened MC903-mediated inflammation, the skin microbiota of Ivl‒/‒ mice was more stable than that of the wild-type mice, which exhibited an MC903-responsive increase in Bacteroidetes and a decrease in Firmicutes. Together, our studies in Ivl‒/‒ mice identify a functional role for IVL to positively impact VDR activity and suggest an emerging IVL/VDR paradigm for adaptation in the human epidermis.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Leptospira interrogans is a bacterial species responsible for leptospirosis, a neglected worldwide zoonosis. Mice and rats are resistant and can become asymptomatic carriers, whereas humans and some other mammals may develop severe forms of leptospirosis. Uncommon among spirochetes, leptospires contain lipopolysaccharide (LPS) in their outer membrane. LPS is highly immunogenic and forms the basis for a large number of serovars. Vaccination with inactivated leptospires elicits a protective immunity, restricted to serovars with related LPS. This protection that lasts in mice, is not long lasting in humans and requires annual boosts. Leptospires are stealth pathogens that evade the complement system and some pattern recognition receptors from the Toll-like (TLR) and Nod-Like families, therefore limiting antibacterial defense. In macrophages, leptospires totally escape recognition by human TLR4, and escape the TRIF arm of the mouse TLR4 pathway. However, very little is known about the recognition and processing of leptospires by dendritic cells (DCs), although they are crucial cells linking innate and adaptive immunity. Here we tested the activation of primary DCs derived from human monocytes (MO-DCs) and mouse bone marrow (BM-DCs) 24h after stimulation with saprophytic or different pathogenic virulent or avirulent L. interrogans. We measured by flow cytometry the expression of DC-SIGN, a lectin involved in T-cell activation, co-stimulation molecules and MHC-II markers, and pro- and anti-inflammatory cytokines by ELISA. We found that exposure to leptospires, live or heat-killed, activated dendritic cells. However, pathogenic L. interrogans, especially from the Icterohaemorraghiae Verdun strain, triggered less marker upregulation and less cytokine production than the saprophytic Leptospira biflexa. In addition, we showed a better activation with avirulent leptospires, when compared to the virulent parental strains in murine BM-DCs. We did not observe this difference in human MO-DCs, suggesting a role for TLR4 in DC stimulation. Accordingly, using BM-DCs from transgenic deficient mice, we showed that virulent Icterohaemorraghiae and Manilae serovars dampened DC activation, at least partly, through the TLR4 and TRIF pathways. This work shows a novel bacterial immune evasion mechanism to limit DC activation and further illustrates the role of the leptospiral LPS as a virulence factor.
Copyright © 2022 Cagliero, Vernel-Pauillac, Murray, Adler, Matsui and Werts.

Tumour-draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre-metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LN-resident LECs was partly dependent on lymphatic VCAM-1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross-presentation on MHC-I, resulting in apoptosis induction in antigen-specific CD8+ T cells. In conclusion, our data identify EV-mediated melanoma-LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.
© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

h4>Background: /h4> Experimental Autoimmune Encephalomyelitis (EAE) is a demyelinating neurological illness having immunological, histological, and clinical parallels to MS (EAE). Cell-to-cell communication and exosomes are two mechanisms through which MSCs exert their effects. The purpose of this study was to see how effective BM-MSCs were at treating EAE patients. h4>Materials: /h4> and Procedures: Myelin Oligodendrocyte Glycoprotein (MOG35-55) was used to induce EAE in C57BL/6 mice (n=32), and then BM-MSCs 1×10 6 cells were administered. Every day, clinical and weight examinations were performed. Histology will be used to assess inflammation and demyelination in mouse CNS parts. Using Real-time PCR, we investigated the expression of pro and anti-inflammatory genes, as well as miRNAs intricate in the differentiation and function of Th cells in the control and progression of EAE. h4>Results: /h4> In the EAE, BM.MSCs significantly reduced clinical symptoms, inflammation, and demyelination of the brain. Our findings suggest that improved expression of miR-193 miR-146a and decreased expression of miR-155 and miR-21 miR-326 was followed by an increase in cytokine expression levels of IL-10, TGF-β, and IL-4; however, IFN-γ and IL-27 levels were reduced in treatment groups. Treatment groups were also associated with suppressing effects on Th1 and Th17 immune responses, induction of Treg cells, and immunoregulatory responses. h4>Conclusions: /h4>: These findings provide compelling evidence that MSC-derived exosomes modulate immune suppression and highlight the significance of BM.MSCs and miRNAs in affecting T cell differentiation and reducing CNS inflammation, demyelination, and local neurodegeneration.