Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms

Abstract

Inflammation is a hallmark of BCR-ABL-negative myeloproliferative neoplasms (MPN), driven by mutations in <em>JAK2</em>, <em>CALR</em>, and <em>MPL</em> 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. <br/>

This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine <em>Jak2V617F</em>- and <em>CALR</em>-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a <em>Jak2V617F</em> MPN mouse model was used to compare wildtype and <em>Nlrp3</em>-deficient animals. <em>Nlrp3</em> deficiency resulted in reduced BM fibrosis, decreased <em>COL1A1</em> expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, <em>Nlrp3</em> deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (<em>Adrb3</em>) expression in the BM. <br/>

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.