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Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae.

ABSTRACT: PTPN6 encodes SHP1, a protein tyrosine phosphatase with an essential role in immune cell function. SHP1 mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in motheaten mice that lack functional SHP1. To investigate the function of Shp1 in developing zebrafish embryos, we generated a ptpn6 knockout zebrafish line lacking functional Shp1. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development, the myeloid lineage was affected, resulting in a decrease in the number of neutrophils and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher in ptpn6 mutants than in siblings at 5 dpf. Finally, the directional migration of neutrophils and macrophages was decreased in response to wounding, and fewer macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impaired neutrophil and macrophage function, and caused severe inflammation and lethality at the larval stage.

SUBMITTER: Allers M

PROVIDER: S-EPMC9922729 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae.

Allers Maaike M Bakker Petra A PA Hoeksma Jelmer J Spaink Herman P HP den Hertog Jeroen J

Disease models & mechanisms 20230130 2

PTPN6 encodes SHP1, a protein tyrosine phosphatase with an essential role in immune cell function. SHP1 mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in motheaten mice that lack functional SHP1. To investigate the function of Shp1 in developing zebrafish embryos, we generated a ptpn6 knockout zebrafish line lacking functional Shp1. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). Du ...[more]

PMID: 36645087

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Project description:Shp1, encoded by the gene Ptpn6, is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro. We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.

Project description:Parkinson's disease is the second most common human neurodegenerative disease. Motor control impairment represents a key clinical hallmark and primary clinical symptom of the disease, which is further characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of α-synuclein aggregations. We have identified major intrinsically disordered NOTCH2-associated receptor 2 encoded by KIAA1024L, a previously uncharacterized protein that is highly conserved in humans and other species. In this study, we demonstrate that major intrinsically disordered NOTCH2-associated receptor 2 expression is significantly down-regulated in the frontal lobe brain of patients with Lewy body dementia. Major intrinsically disordered NOTCH2-associated receptor 2 is predominantly expressed in brain tissue and is particularly prominent in the midbrain. Major intrinsically disordered NOTCH2-associated receptor 2 interacts with neurogenic locus notch homologue protein 2 and is localized at the endoplasmic reticulum compartments. We generated major intrinsically disordered NOTCH2-associated receptor 2 knockout mouse and demonstrated that the loss of major intrinsically disordered NOTCH2-associated receptor 2 in mouse results in severe motor deficits such as rigidity and bradykinesia, gait abnormalities, reduced spontaneous locomotor and exploratory behaviour, symptoms that are highly similar to those observed in human Parkinson's spectrum disorders. Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in α-synuclein protein expression. Taken together, these data demonstrate a previously unknown function for major intrinsically disordered NOTCH2-associated receptor 2 in the pathogenesis of Parkinson's spectrum disorders.

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Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae.

Publications

Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae.

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