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PTP1B Deficiency in Myeloid Cells Increases Susceptibility to Candida albicans Infection by Modulating Anti-fungal Immunity

ABSTRACT: Invasive candidiasis is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Understanding how the immune response towards Candida albicans is mounted and controlled is fundamental to developing new therapeutic strategies. Protein tyrosine phosphatase 1B (PTP1B) is a key phosphatase regulating various immunoreceptor signalling cascades including inflammatory and metabolic responses and a pharmaceutical target. This study uncovers the importance of PTP1B in driving protective antifungal immune cell responses post-infection. Following systemic C. albicans infection, mice lacking PTP1B in myeloid cells (LysM PTP1B-/-) were significantly more susceptible to infection, with lower survival rates, greater body weight loss and higher fungal burdens in brain, kidney, and liver. LysM PTP1B-/- infected mice exhibited increased expression of organ inflammatory cytokines TNF, IL-10, IL-6 and IL-1β and increased kidney tubular inflammation, 1- and 3-days post-infection. Kidneys from infected LysM PTP1B-/- mice also demonstrated significantly increased chemokine expression and leukocyte infiltration, collectively promoting immunopathology. PTP1B-/- neutrophils infiltrating into kidneys were, however, less mature and in vitro produced less ROS. Bone marrow-derived macrophages from LysM PTP1B-/- mice, through proteomic analysis, show enhancement of immune response and type I interferon signalling pathways, and they were less able to phagocytose and kill C. albicans relating to changes in their metabolism and viability when fighting infection. The decrease in phagocytosis and viability in PTP1B-/- macrophages following infection translated to human macrophages treated with a pharmacological PTP1B inhibitor. Our data provides new insights connecting the critical role of myeloid cell PTP1B in regulating immune defence against C. albicans through modulating levels of inflammatory cytokines, neutrophil clearance mechanisms and macrophage functional and metabolic responses, implying that boosting specific PTP1B-dependent signalling pathways could have therapeutic implications for combatting systemic fungal infection.

INSTRUMENT(S):

ORGANISM(S): Candida Albicans (yeast) Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture, Cell Culture, Bone Marrow, Macrophage

SUBMITTER: Alan Score

LAB HEAD: J Simon C Arthur

PROVIDER: PXD057300 | Pride | 2025-08-28

REPOSITORIES: Pride

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			Action	DRS
	260_2023_CB-Sample-10.raw	Raw
	260_2023_CB-Sample-11.raw	Raw
	260_2023_CB-Sample-12.raw	Raw
	260_2023_CB-Sample-13.raw	Raw
	260_2023_CB-Sample-14.raw	Raw

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Project description:The model is first model of tissue level cellular immune responses to H. pylori in the publication, "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

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PTP1B Deficiency in Myeloid Cells Increases Susceptibility to Candida albicans Infection by Modulating Anti-fungal Immunity

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