Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms
Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms
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DissertationDate of Exam
22.09.2025Date of Publication
02.10.2025Advisor
Brossart, PeterCo-Referee
Jansen, ChristianMetadata
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Abstract
Inflammation is a hallmark of BCR-ABL-negative myeloproliferative neoplasms (MPN), driven by mutations in JAK2, CALR, and MPL that activate JAK-STAT signaling and induce pro-inflammatory cytokines. Interleukin-1β (IL-1β), regulated by the NLRP3 inflammasome, has been implicated in key pathological features of MPN, including bone marrow (BM) fibrosis, neuropathy, and mesenchymal stem cell (MSC) loss.
This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine Jak2V617F- and CALR-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a Jak2V617F MPN mouse model was used to compare wildtype and Nlrp3-deficient animals. Nlrp3 deficiency resulted in reduced BM fibrosis, decreased COL1A1 expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, Nlrp3 deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (Adrb3) expression in the BM.
Together, these findings identify the NLRP3 inflammasome as a critical contributor to MPN pathology and support its potential as a therapeutic target. Inhibiting inflammasome activity may represent a novel strategy to improve outcomes for patients with BCR-ABL-negative MPN.
This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine Jak2V617F- and CALR-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a Jak2V617F MPN mouse model was used to compare wildtype and Nlrp3-deficient animals. Nlrp3 deficiency resulted in reduced BM fibrosis, decreased COL1A1 expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, Nlrp3 deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (Adrb3) expression in the BM.
Together, these findings identify the NLRP3 inflammasome as a critical contributor to MPN pathology and support its potential as a therapeutic target. Inhibiting inflammasome activity may represent a novel strategy to improve outcomes for patients with BCR-ABL-negative MPN.
Subjects
Myeloproliferative neoplasms (MPN), JAK2V617F, Inflammation, NLRP3 inflammasome, Interleukin-1β (IL-1β), Bone marrow fibrosis, Megakaryopoiesis, Neuropathy, Mesenchymal stem cells (MSC)
Classification (DDC)
610 Medizin, GesundheitTregel, Elisabeth Rosina Ursula: Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms. - Bonn, 2025. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-85493
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-85493
@phdthesis{handle:20.500.11811/13497,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-85493,
author = {{Elisabeth Rosina Ursula Tregel}},
title = {Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = oct,
note = {Inflammation is a hallmark of BCR-ABL-negative myeloproliferative neoplasms (MPN), driven by mutations in JAK2, CALR, and MPL that activate JAK-STAT signaling and induce pro-inflammatory cytokines. Interleukin-1β (IL-1β), regulated by the NLRP3 inflammasome, has been implicated in key pathological features of MPN, including bone marrow (BM) fibrosis, neuropathy, and mesenchymal stem cell (MSC) loss.
This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine Jak2V617F- and CALR-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a Jak2V617F MPN mouse model was used to compare wildtype and Nlrp3-deficient animals. Nlrp3 deficiency resulted in reduced BM fibrosis, decreased COL1A1 expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, Nlrp3 deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (Adrb3) expression in the BM.
Together, these findings identify the NLRP3 inflammasome as a critical contributor to MPN pathology and support its potential as a therapeutic target. Inhibiting inflammasome activity may represent a novel strategy to improve outcomes for patients with BCR-ABL-negative MPN.},
url = {https://hdl.handle.net/20.500.11811/13497}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-85493,
author = {{Elisabeth Rosina Ursula Tregel}},
title = {Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = oct,
note = {Inflammation is a hallmark of BCR-ABL-negative myeloproliferative neoplasms (MPN), driven by mutations in JAK2, CALR, and MPL that activate JAK-STAT signaling and induce pro-inflammatory cytokines. Interleukin-1β (IL-1β), regulated by the NLRP3 inflammasome, has been implicated in key pathological features of MPN, including bone marrow (BM) fibrosis, neuropathy, and mesenchymal stem cell (MSC) loss.
This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine Jak2V617F- and CALR-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a Jak2V617F MPN mouse model was used to compare wildtype and Nlrp3-deficient animals. Nlrp3 deficiency resulted in reduced BM fibrosis, decreased COL1A1 expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, Nlrp3 deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (Adrb3) expression in the BM.
Together, these findings identify the NLRP3 inflammasome as a critical contributor to MPN pathology and support its potential as a therapeutic target. Inhibiting inflammasome activity may represent a novel strategy to improve outcomes for patients with BCR-ABL-negative MPN.},
url = {https://hdl.handle.net/20.500.11811/13497}
}
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