Tfh cells with NLRP3 inflammasome activation are essential for high-affinity antibody generation, germinal centre formation and autoimmunity

Abstract

ObjectiveNLRP3 inflammasome regulates T cell responses. This study examined the roles of NLRP3 inflammasome activation in the regulation of T follicular helper (Tfh) cells during humoral response to T dependent antigens and in systemic lupus erythematosus (SLE).MethodsNLRP3 inflammasome activation of Tfh cells was studied in B6, MRL/lpr and NZM2328 mice and in SLE patients and healthy controls using a fluorescence-labelled caspase-1 inhibitor probe. MCC950, a selective inhibitor of NLRP3, was used to investigate the relation between NLRP3 inflammasome activation and germinal centre (GC) reaction, Ab responses to immunisation, and autoantibody production.ResultsNLRP3 inflammasome activation in Tfh cells after immunisation was identified in B6 mice. MCC950 inhibited humoral responses to sheep red blood cell and NP-CGG with reduction of the GC reaction. B6 mice with lymphoid cell-specific deletion of NLRP3 or Casp1 mounted suboptimal humoral responses with impaired GC formation and defective affinity maturation. In MRL/lpr and NZM2328 mice, inhibition of NLRP3 activation suppressed NLRP3 activated Tfh cell expansion as well as attenuated lupus-like phenotypes. Tfh cells with activated NLRP3 inflammasome exhibited increased expression of molecules for Tfh cell function and differentiation, and had greater ability to activate B cells. In SLE patients, disease activity was positively correlated with an increase in the activated NLRP3+ Tfh population and this population was markedly reduced in response to therapy.ConclusionsThe activation of NLRP3 inflammasome in Tfh cells is an integral part of responses to immunisation. The activated NLRP3+ Tfh population is essential for optimal humoral responses, GC formation and autoimmunity.

Identification and immuno-infiltration analysis of cuproptosis regulators in human atherosclerosis

“…The activation of the NLRP3 in ammasome in T follicular helper cells is a component of the immune response. (35) Increased expression of CDKN2A expression is associated with the appearance of immune senescence phenotypic changes in lymphocyte subpopulations. (36) Therefore, considering the ndings of previous studies in conjunction with the results of our study, we postulate that cuproptosis is related to immune in ltration in AS.…”

Role of adenosine A2a receptor in cancers and autoimmune diseases

“…Systemic lupus erythematosus (SLE) is a typical autoimmune disease that produces a large number of autoantibodies and involves multiple organs. The etiology of SLE has not yet been fully clarified, and studies have shown that the immune system dysfunction is related to pathogenesis of this disease 79,80 . Higher levels of A2AR expression were found on T cells in SLE patients compared to healthy controls and were inversely correlated with disease activity 58 .…”

“…The etiology of SLE has not yet been fully clarified, and studies have shown that the immune system dysfunction is related to pathogenesis of this disease. 79,80 Higher levels of A2AR expression were found on T cells in SLE patients compared to healthy controls and were inversely correlated with disease activity. 58 Moreover, activation of A2AR reduces the NF-κB signaling and diminishes production of inflammatory cytokines (IL-1β, IL-6, IFNα, TNF), increasing the anti-inflammatory cytokine IL-10 release.…”

Mechanism of NLRP3 inflammasome intervention for synovitis in knee osteoarthritis: A review of TCM intervention

“…NLRP3 exists in the cytoplasm and participates in innate immunity as PRRs. It is activated by recognizing PAMPs and DAMPs ( Zhao et al, 2022a ). NLRP3 inflammasome consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and Pro-caspase-1 ( Zahid et al, 2019 ).…”