The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation

Abstract

NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1β and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

Clodronate liposomes may biases MSC differentiation toward adipogenesis through activation of NLRP3

“…We speculate that the increase in adipocytes may be related to the activation of the NLRP3/Caspase-1 pathway. Post-transplant recipients are prone to complications, and NLRP3 activation plays a key role in the development of transplant complications [ 22 ]. Inflammasomes are large multimeric protein complexes that mediate rapid immune responses to pathogen infection and tissue injury and are composed of NLRP1, NLRP2, NLRP3, NLRP6 and NLRC4, with NLRP3 being one of the most studied inflammasomes in the field of immunometabolism [ 23 ].…”

New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation

“…This can be achieved by increasing BM noradrenergic innervation to promote b2-adrenergic-receptor (AR)-interleukin-6-dependent megakaryopoiesis, reducing b3-AR-Nos1 activity. Increased b2-AR activity enhances IL-6-dependent myeloid differentiation [ 27 ]. Meanwhile, decreased b3-AR-Nos1-NO can reduce endosteal niches and increase central niches.…”

Molecular Immunology in Hematological Disorders

“…Therefore, there is a close pathophysiological relationship between hematological diseases and the immune system, and the elucidation of these molecular mechanisms will advance the diagnosis and treatment of benign and malignant hematologic, infectious, and autoimmune diseases. Contemporary studies [ 1 , 2 , 3 , 4 , 5 , 6 ] have focused on the applications of molecular immunology in hematology, providing fresh insights into the molecular immunological mechanisms involved in the diagnosis and treatment of hematologic diseases.…”

“…Although allogeneic hematopoietic stem cell transplantation can effectively treat leukemia through the graft-versus-leukemia (GVL) effect, it is currently difficult to avoid conditioning-related toxicity, severe infections, graft-versus-host disease (GVHD), and their associated mortality and morbidity [ 7 , 8 , 9 , 10 , 11 , 12 ]. Observations made by Espinoza et al [ 6 ] may overcome this dilemma. The study showed that the gene encoding the NLR family pyrin domain-containing 3 (NLRP3) protein, which plays pivotal roles in innate immune responses, exhibits a functional polymorphism, and transplant recipients with the NLRP3 gene polymorphisms that overexpress NLRP3 were more likely to induce the production of IL-1b than other transplant recipients, leading to increased transplant-related mortality.…”