Publikasjoner
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Sanchez, Alberto Diez; Lindholm, Håvard Takle; Vornewald, Pia Magdalena; Ostrop, Jenny; Yao, Rouan & Single, Andrew Bruce
[Vis alle 11 forfattere av denne artikkelen]
(2024).
LSD1 drives intestinal epithelial maturation and controls small intestinal immune cell composition independent of microbiota in a murine model.
Nature Communications.
15:3412(1),
s. 1–20.
doi:
10.1038/s41467-024-47815-2.
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Postnatal development of the gastrointestinal tract involves the establishment of the commensal microbiota, the acquisition of immune tolerance via a balanced immune cell composition, and maturation of the intestinal epithelium. While studies have uncovered an interplay between the first two, less is known about the role of the maturing epithelium. Here we show that intestinal-epithelial intrinsic expression of lysine-specific demethylase 1A (LSD1) is necessary for the postnatal maturation of intestinal epithelium and maintenance of this developed state during adulthood. Using microbiota-depleted mice, we find plasma cells, innate lymphoid cells (ILCs), and a specific myeloid population to depend on LSD1-controlled epithelial maturation. We propose that LSD1 controls the expression of epithelial-derived chemokines, such as Cxcl16, and that this is a mode of action for this epithelial-immune cell interplay in local ILC2s but not ILC3s. Together, our findings suggest that the maturing epithelium plays a dominant role in regulating the local immune cell composition, thereby contributing to gut homeostasis.
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Vornewald, Pia Magdalena; Forman, Ruth; Yao, Rouan; Parmar, Naveen; Lindholm, Håvard Takle & Lee, Lilith Sian Kaspersen
[Vis alle 9 forfattere av denne artikkelen]
(2023).
Mmp17- deficient mice exhibit heightened goblet cell effector expression in the colon and increased resistance to chronic Trichuris muris infection.
Frontiers in Immunology.
14:1243528,
s. 1–16.
doi:
10.3389/fimmu.2023.1243528.
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Intestinal epithelial homeostasis is maintained by intrinsic and extrinsic signals. The extrinsic signals include those provided by mesenchymal cell populations that surround intestinal crypts and is further facilitated by the extracellular matrix (ECM), which is modulated by proteases such as matrix metalloproteinases (MMPs). Extrinsic signals ensure an appropriate balance between intestinal epithelial proliferation and differentiation. This study explores the role of MMP17, which is preferentially expressed by smooth muscle cells in the intestine, in intestinal homeostasis and during immunity to infection. Mice lacking MMP17 expressed high levels of goblet-cell associated genes and proteins, such as CLCA1 and RELM-β, which are normally associated with immune responses to infection. Nevertheless, Mmp17 KO mice did not have altered resistance during a bacterial Citrobacter rodentium infection. However, when challenged with a low dose of the helminth Trichuris muris, Mmp17 KO mice had increased resistance, without a clear role for an altered immune response during infection. Mechanistically, we did not find changes in traditional modulators of goblet cell effectors such as the NOTCH pathway or specific cytokines. We found MMP17 expression in smooth muscle cells as well as lamina propria cells such as macrophages. Together, our data suggest that MMP17 extrinsically alters goblet cell maturation which is sufficient to alter clearance in a helminth infection model.
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Das, Saykat; Stamnæs, Jorunn; Kemppainen, Esko; Hervonen, Kaisa; Lundin, Knut & Parmar, Naveen
[Vis alle 12 forfattere av denne artikkelen]
(2023).
Separate Gut Plasma Cell Populations Produce Auto-Antibodies against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis.
Advanced Science.
10:2300401(25),
s. 1–10.
doi:
10.1002/advs.202300401.
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Abstract Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto‐antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto‐antibodies are specific for either TG2 or TG3 with no TG2–TG3 cross reactivity. By generating monoclonal antibodies from TG3‐specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2‐specific and TG3‐specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase‐reactive populations show distinct selection of certain heavy and light chain V‐genes. Mass spectrometry analysis of TG3‐specific serum IgA corroborates preferential usage of IGHV2‐5 in combination with IGKV4‐1 . Collectively, these results demonstrate parallel induction of anti‐TG2 and anti‐TG3 auto‐antibody responses involving separate B‐cell populations in DH patients.
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Lindholm, Håvard Takle; Parmar, Naveen; Drurey, Claire; Poveda, Marta Campillo; Vornewald, Pia & Ostrop, Jenny
[Vis alle 9 forfattere av denne artikkelen]
(2022).
BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia.
Science immunology.
7(71).
doi:
10.1126/sciimmunol.abl6543.
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Intestinal parasite infections or allergic reactions promote IL-13–induced differentiation of tuft cells as one manifestation of type 2 immunity in the gut. Using organoid cultures of intestinal epithelial cells, Lindholm et al. investigated how the lymphocyte cytokines IL-13, IL-22, and IFNγ regulate the signaling pathways that influence epithelial differentiation. While tuft cell IL-25 promoted expansion of IL-13–producing ILC2s in a feed-forward loop, the resulting IL-13 also induced ligands of the bone morphogenetic protein (BMP) signaling pathway. BMP agonists acted on stem cells to prevent runaway tuft cell expansion by limiting expression of Sox4, a transcription factor required for tuft cell differentiation. These findings provide new molecular insights into how intestinal epithelial differentiation is carefully choreographed in response to a diverse array of cytokine signals.
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Parmar, Naveen; Burrows, Kyle; Vornewald, Pia; Lindholm, Håvard Takle; Zwiggelaar, Rosalie Theda Margien & Sanchez, Alberto Diez
[Vis alle 12 forfattere av denne artikkelen]
(2021).
Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection.
PLoS Pathogens.
ISSN 1553-7366.
17(3).
doi:
10.1371/JOURNAL.PPAT.1009476.
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Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection.
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Parmar, Naveen; Chandrakar, Pragya & Kar, Susanta
(2020).
Leishmania donovani Subverts Host Immune Response by Epigenetic Reprogramming of Macrophage M(Lipopolysaccharides + IFN-g)/M(IL-10) Polarization.
Journal of Immunology.
ISSN 0022-1767.
204(10),
s. 2762–2778.
doi:
10.4049/jimmunol.1900251.
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Zwiggelaar, Rosalie; Lindholm, Håvard Takle; Fosslie, Madeleine Lystad; Pedersen, Marianne Terndrup; Ohta, Yuki & Sanchez, Alberto Diez
[Vis alle 20 forfattere av denne artikkelen]
(2020).
LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium.
Science Advances.
6(37).
doi:
10.1126/sciadv.abc0367.
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Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.
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Publisert
16. juni 2025 10:24
- Sist endret
16. juni 2025 10:24
