| 1. |
- Soehnlein, Oliver, et al.
(author)
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Neutrophil secretion products pave the way for inflammatory monocytes
- 2008
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 112:4, s. 1461-1471
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Journal article (peer-reviewed)abstract
- The leukocyte response in inflammation is characterized by an initial recruitment of polymorphonuclear leukocytes (PMN) preceding a second wave of monocytes to the site of injury or infection. In the mouse, 2 populations of monocytes have been identified, Gr1-CCR2-CX3CR1(hi) resident monocytes and Gr1+CCR2+CX3CR1(lo) inflammatory monocytes. Here, intravital microscopy of the musculus cremasterand a subcutaneous air pouch model were used to investigate a possible link between PMN extravasation and the subsequent emigration of inflammatory monocytes in response to local stimulation with PAR In mice that were made neutropenic by injection of a PMN-depleting antibody, the extravasation of inflammatory monocytes, but not resident monocytes, was markedly reduced compared with mice with intact white blood cell count but was restored by local treatment with secretion of activated PMN. Components of the PMN secretion were found to and further examination revealed PMN-derived LL-37 and heparin-binding protein (HBP/CAP37/azurocidin) as primary mediators of the recruitment of inflammatory monocytes via activation of formyl-peptide receptors. These data show that LL-37 and HBP specifically stimulate mobilization of inflammatory monocytes. This cellular cross-talk functionally results in enhanced cytokine levels and increased bacterial clearance, thus boosting the early immune response.
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| 2. |
- Carow, Berit, et al.
(author)
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Immune mapping of human tuberculosis and sarcoidosis lung granulomas
- 2024
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In: FRONTIERS IN IMMUNOLOGY. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas "multifocal" granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40-60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68, CD14, ITGAM, ITGAX, and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients.
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| 3. |
- Carow, Berit, et al.
(author)
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Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 mu m in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.
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| 4. |
- Eriksson, Emma, et al.
(author)
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CD44-regulated intracellular proliferation of Listeria monocytogenes.
- 2003
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In: Infect Immun. - 0019-9567. ; 71:7, s. 4102-11
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Journal article (other academic/artistic)abstract
- CD44 has been implicated in immune and inflammatory processes. We have analyzed the role of CD44 in the outcome of Listeria monocytogenes infection in murine bone marrow-derived macrophages (BMM). Surprisingly, a dramatically decreased intracellular survival of L. monocytogenes was observed in CD44(-/-) BMM. CD44(-/-) heart or lung fibroblast cultures also showed reduced bacterial levels. Moreover, livers from CD44(-/-)-infected mice showed diminished levels of L. monocytogenes. In contrast, intracellular growth of Salmonella enterica serovar Typhimurium was the same in CD44(-/-) and control BMM. The CD44-mediated increased bacterial proliferation was not linked to altered BMM differentiation or to secretion of soluble factors. CD44 did not mediate listerial uptake, and it played no role in bacterial escape from the primary phagosome or formation of actin tails. Furthermore, CD44-enhanced listerial proliferation occurred in the absence of intracellular bacterial spreading. Interestingly, coincubation of BMM with hyaluronidase or anti-CD44 antibodies that selectively inhibit hyaluronan binding increased intracellular listerial proliferation. Treatment of cells with hyaluronan, in contrast, diminished listerial growth and induced proinflammatory transcript levels. We suggest that L. monocytogenes takes advantage of the CD44-mediated signaling to proliferate intracellularly, although binding of CD44 to certain ligands will inhibit such response.
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| 5. |
- Gao, Yu, et al.
(author)
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SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell Development
- 2021
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Journal article (peer-reviewed)abstract
- The suppressor of cytokine signaling 3 (SOCS3) is a major regulator of immune responses and inflammation as it negatively regulates cytokine signaling. Here, the role of SOCS3 in thymic T cell formation was studied in Socs3fl/fl Actin-creER mice (Δsocs3) with a tamoxifen inducible and ubiquitous Socs3 deficiency. Δsocs3 thymi showed a 90% loss of cellularity and altered cortico-medullary organization. Thymocyte differentiation and proliferation was impaired at the early double negative (CD4-CD8-) cell stage and apoptosis was increased during the double positive (CD4+CD8+) cell stage, resulting in the reduction of recent thymic emigrants in peripheral organs. Using bone marrow chimeras, transplanting thymic organoids and using mice deficient of SOCS3 in thymocytes we found that expression in thymic stromal cells rather than in thymocytes was critical for T cell development. We found that SOCS3 in thymic epithelial cells (TECs) binds to the E3 ubiquitin ligase TRIM 21 and that Trim21−/− mice showed increased thymic cellularity. Δsocs3 TECs showed alterations in the expression of genes involved in positive and negative selection and lympho-stromal interactions. SOCS3-dependent signal inhibition of the common gp130 subunit of the IL-6 receptor family was redundant for T cell formation. Together, SOCS3 expression in thymic stroma cells is critical for T cell development and for maintenance of thymus architecture.
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| 6. |
- Lu, Jun, et al.
(author)
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Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei
- 2013
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:38, s. 27456-27468
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Journal article (peer-reviewed)abstract
- Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.
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| 7. |
- Magoulopoulou, Anastasia, et al.
(author)
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Spatial Resolution of Mycobacterium tuberculosis Bacteria and Their Surrounding Immune Environments Based on Selected Key Transcripts in Mouse Lungs
- 2022
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Journal article (peer-reviewed)abstract
- Mycobacterium tuberculosis (Mtb) bacilli are the causative agent of tuberculosis (TB), a major killer of mankind. Although it is widely accepted that local interactions between Mtb and the immune system in the tuberculous granuloma determine whether the outcome of infection is controlled or disseminated, these have been poorly studied due to methodological constraints. We have recently used a spatial transcriptomic technique, in situ sequencing (ISS), to define the spatial distribution of immune transcripts in TB mouse lungs. To further contribute to the understanding of the immune microenvironments of Mtb and their local diversity, we here present two complementary automated bacteria-guided analysis pipelines. These position 33 ISS-identified immune transcripts in relation to single bacteria and bacteria clusters. The analysis was applied on new ISS data from lung sections of Mtb-infected C57BL/6 and C3HeB/FeJ mice. In lungs from C57BL/6 mice early and late post infection, transcripts that define inflammatory macrophages were enriched at subcellular distances to bacteria, indicating the activation of infected macrophages. In contrast, expression patterns associated to antigen presentation were enriched in non-infected cells at 12 weeks post infection. T-cell transcripts were evenly distributed in the tissue. In Mtb-infected C3HeB/FeJ mice, transcripts characterizing activated macrophages localized in apposition to small bacteria clusters, but not in organized granulomas. Despite differences in the susceptibility to Mtb, the transcript patterns found around small bacteria clusters of C3HeB/FeJ and C57BL/6 mice were similar. Altogether, the presented tools allow us to characterize in depth the immune cell populations and their activation that interact with Mtb in the infected lung.
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| 8. |
- Pawlowski, Andrzej, et al.
(author)
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Tuberculosis and HIV Co-Infection
- 2012
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 8:2
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Research review (peer-reviewed)abstract
- Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism. We also review possible animal models for studies of the interaction of the two pathogens, and describe gaps in knowledge and needs for future studies to develop preventive measures against the two diseases.
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| 9. |
- Rauch, Katharina S., et al.
(author)
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Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a TranscriptionalNetwork of E47, Spi-B, and SOCS3
- 2016
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In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 17:11, s. 2827-2836
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Journal article (peer-reviewed)abstract
- The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.
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| 10. |
- Vodnala, Suman K., et al.
(author)
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In Vitro and In Vivo Activities of 2-Aminopyrazines and 2-Aminopyridines in Experimental Models of Human African Trypanosomiasis
- 2013
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 57:2, s. 1012-1018
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Journal article (peer-reviewed)abstract
- New drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for Trypanosoma brucei subsp. brucei viability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)]oxy)-N-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for T. brucei subsp. brucei, T. brucei subsp. gambiense, and T. brucei subsp. rhodesiense and is nontoxic to mammalian cell lines, and in vitro preclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with T. brucei subsp. brucei, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.
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