Dendritic cells (DCs) present exogenous antigens via major histocompatibility complex class I (MHC-I) and MHC class II (MHC-II) molecules, activating CD8+ and CD4+ T cells. A critical but poorly understood step in this process is the trafficking of peptide-loaded MHC molecules from the endocytic system to the cell surface. In this study, we demonstrate that the Golgi reassembly-stacking protein of 55 kDa (GRASP55), which has been shown to have no role in stacking, is essential for antigen presentation. Using soluble, bead-coated, and bacterial-bound antigens, we found significantly impaired exogenous antigen presentation in GRASP55-deficient bone-marrow-derived DCs (BMDCs). Notably, GRASP55 was recruited to late phagosomes, and our data suggest that it is crucial for sorting MHC-I and MHC-II molecules, facilitating their trafficking to the plasma membrane. Our findings highlight the vital role of GRASP55 in the intracellular transport of MHC molecules bound to their respective peptides during exogenous antigen presentation.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.
Published by Elsevier Inc.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients. The authors find that 7α, 25-OHC binding to its receptor Epstein-Barr virus-induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN-β, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN-γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2-deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane-induced SLE. Together, via sensing the oxysterol 7α, 25-OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTIs). Studies examining the immune response to S. aureus have been conducted, yet our understanding of the kinetic response to S. aureus subcutaneous skin infection remains incomplete. In this study, we used C57BL/6J mice and USA300 S. aureus to examine the host-pathogen interface from 8 h postinfection to 15 days postinfection (dpi), with the following outcomes measured: lesion size, bacterial titers, local cytokine and chemokine levels, phenotype of the responding leukocytes, and histopathology and Gram staining of skin tissue. Lesions were largest at 1 dpi, with peak necrotic tissue areas at 3 dpi, and were largely resolved by 15 dpi. During early infection, bacterial titers were high, neutrophils were the most abundant immune cell type, there was a decrease in most leukocyte populations found in uninfected skin, and many different cytokines were produced. Histopathological analysis demonstrated swift and extensive keratinocyte death and robust and persistent neutrophil infiltration. Gram staining revealed subdermal S. aureus colonization and, later, limited migration into upper skin layers. Interleukin-17A/F (IL-17A/F) was detected only starting at 5 dpi and coincided with an immediate decrease in bacterial numbers in the following days. After 9 days, neutrophils were no longer the most abundant immune cell type present as most other leukocyte subsets returned, and surface wounds resolved coincident with declining bacterial titers. Collectively, these data illustrate a dynamic immune response to S. aureus skin infection and suggest a key role for precisely timed IL-17 production for infection clearance and healthy tissue formation.

In multiple sclerosis (MS), abnormally activated immune cells responsive to myelin proteins result in widespread damage throughout the central nervous system (CNS) and ultimately irreversible disability. Immunomodulation by delivering dendritic cells (DCs) utilizes a potent and rapid MS disease progression driver therapeutically. Here, we investigated delivering DCs for disease severity attenuation using an experimental autoimmune encephalomyelitis preclinical MS model. DCs treated with interleukin-10 (IL-10) (DC10s) were transplanted using in situ gelling poly(ethylene glycol)-based hydrogel for target site localization. DC delivery increased hydrogel longevity and altered the injection site recruited, endogenous immune cell profile within 2 days postinjection. Furthermore, hydrogel-mediated DC transplantation efficacy depended on the injection-site. DCs delivered to the neck local to MS-associated CNS-draining cervical lymph nodes attenuated paralysis, compared to untreated controls, while delivery to the flank did not alter paralysis severity. This study demonstrates that local delivery of DC10s modulates immune cell recruitment and attenuates disease progression in a preclinical model of MS.
© 2020 Wiley Periodicals LLC.