NLRP3 negatively regulates Treg differentiation through Kpna2-mediated nuclear translocation

Abstract

Edited by Luke O'Neill Naïve CD4 ؉ T cells in the periphery differentiate into regulatory T cells (Tregs) in which Foxp3 is expressed for their suppressive function. NLRP3, a pro-inflammatory molecule, is known to be involved in inflammasome activation associated with several diseases. Recently, the expression of NLRP3 in CD4 ؉ T cells, as well as in myeloid cells, has been described; however, a role of T cell-intrinsic NLRP3 in Treg differentiation remains unknown. Here, we report that NLRP3 impeded the expression of Foxp3 independent of inflammasome activation in Tregs. NLRP3-deficient mice elevate Treg generation in various organs in the de novo pathway. NLRP3 deficiency increased the amount and suppressive activity of Treg populations, whereas NLRP3 overexpression reduced Foxp3 expression and Treg abundance. Importantly, NLRP3 interacted with Kpna2 and translocated to the nucleus from the cytoplasm under Tregpolarizing conditions. Taken together, our results identify a novel role for NLRP3 as a new negative regulator of Treg differentiation, mediated via its interaction with Kpna2 for nuclear translocation.

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

“…Because HCC occurs almost exclusively in the context of chronic inflammation (Ringelhan et al, 2018), further understanding of the associations of immune response would provide new clues for HCC diagnosis and therapy. Although KPNA2 was implicated in many inflammatory processes (Liu et al, 2015;Pallett et al, 2019;Park et al, 2019), and its tumor-promoting activities in HCC (Gao et al, 2018;Lin et al, 2018;Zan et al, 2019) were shown in many studies, its associations with immune response in HCC and their clinical significance were not clearly illustrated. Here, we not only confirmed the upregulation and unfavorable prognostic effects of KPNA2 in HCC, and through further systemic analyses of its correlations with immune cell infiltrations in HCC tumors and normal liver tissues individually, we presented the specific positive correlation between KPNA2 expression and B-cell infiltration in the tumors.…”

“…In rheumatoid arthritis, KPNA2 was shown to be a trigger of interleukin 6 (IL-6) secretion, colocalized with T cells and neutrophils, and could be upregulated via tumor necrosis factor α stimulation (Liu et al, 2015). It was also demonstrated to play crucial roles in the negative regulation of regulatory T cells (Tregs) differentiation through its interaction and translocation of proinflammatory molecule NLRP3 (Park et al, 2019). In a study of vaccinia virus (VACV), the positive effects of KPNA2 on immunoregulation was shown in the induction of VACV specific CD8 + T-cell memory via its interaction with p65 (Pallett et al, 2019).…”

Upregulation of Nucleotide-Binding Oligomerization Domain-, LRR- and Pyrin Domain-Containing Protein 3 in Motoneurons Following Peripheral Nerve Injury in Mice

“…In the nucleus, activated caspase-1 may have other substrates than pro-IL-1β and pro-IL-18, e.g., sirtuin-1. Besides participating in the formation of inflammasomes, nuclear NLRs may have other functions as well, e.g., NLRP3 is a transcriptional regulator in T helper type 2 cells and a repressor of regulatory T cell differentiation (Bruchard et al, 2015;Park et al, 2020). It is not known yet, whether beyond serving as a receptor in inflammasomes, NLRP3 has any regulatory functions in neurons.…”

Protectin DX restores Treg/Th17 cell balance in rheumatoid arthritis by inhibiting NLRP3 inflammasome via miR-20a

“…In a recent study, Yu et al confirmed that NLRP3 activation promotes differentiation of T h 17 cells in mice with lupus 17 . Meanwhile, Park et al demonstrated that NLRP3 negatively regulates Treg differentiation through karyopherin subunit alpha 2 (KPNA2)–mediated nuclear translocation 18 . These facts suggested that NLRP3 might participate in the regulation of Treg/T h 17 cell balance.…”