Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1β secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow–derived macrophages. The inhibitory effect of curcumin on inflammasome activation was specific to the NLRP3, not to the NLRC4 or the AIM2 inflammasomes. Curcumin inhibited the NLRP3 inflammasome by preventing K⁺ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation. Reactive oxygen species, autophagy, sirtuin-2, or acetylated α-tubulin was ruled out as the mechanism by which curcumin inhibits the inflammasome. Importantly, in vivo data show that curcumin attenuated IL-1β secretion and prevented high-fat diet–induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice. Curcumin also repressed monosodium urate crystal–induced peritoneal inflammation in vivo. Taken together, we identified curcumin as a common NLRP3 inflammasome activation inhibitor. Our findings reveal a mechanism through which curcumin represses inflammation and suggest the potential clinical use of curcumin in NLRP3-driven diseases.

Background Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder, in which platelet glycoprotein (GP)IIb–IIIa and GPIb–IX are the two most frequently targeted autoantigens. Our previous studies in animal models of ITP demonstrated that intravenous immunoglobulin G (IVIG) could protect against anti‐GPIIb–IIIa autoantibody‐mediated thrombocytopenia but failed to ameliorate ITP induced by most anti‐GPIb–IX autoantibodies. Objectives The objective of this human study was to evaluate the association between the specificity of antiplatelet autoantibodies and response to IVIG treatment. Patients/Methods In this retrospective study, a cohort of 156 previously untreated adults with severe ITP who underwent IVIG therapy (0.4 g kg⁻¹ day⁻¹ for 5 days) was analyzed. The primary outcome was response defined as platelet counts of ≥ 30 × 10⁹ L⁻¹ and a doubling of baseline counts within 7 days of dosing, and an absence of bleeding. Results and Conclusions Among the 66 patients with anti‐GPIb–IX autoantibodies, only 24 (36.4%) achieved a response, as compared with 72 of 90 patients (80.0%) who were negative for anti‐GPIb–IX autoantibodies (relative risk 2.2; 95% confidence interval 1.6–3.1). This study found no difference in response between patients with anti‐GPIIb–IIIa autoantibodies (61.7%) and those without anti‐GPIIb–IIIa autoantibodies (61.3%). Logistic regressions, including main effects and the interaction between these two autoantibodies, showed no influence of anti‐GPIIb–IIIa autoantibodies on the effects of anti‐GPIb–IX autoantibodies with regard to their association with IVIG response. Thus, in adults with ITP, the presence of anti‐GPIb–IX autoantibodies is a predictive factor for poor response to IVIG treatment. Trial registration: ClinicalTrials.gov NCT01666795.

Essentials M1/M2 imbalance is involved in many autoimmune diseases, and could be restored. The expressions and functions of M1 and M2 were investigated in an in vitro culture system. A preferred M1 polarization is involved in the pathogenesis of immune thrombocytopenia (ITP). High‐dose dexamethasone or all‐trans‐retinoic acid restores M1/M2 balance in ITP patients. Summary Background Immune thrombocytopenia (ITP) is an autoimmune disorder. Deficiency of immune tolerance in antigen‐presenting cells and cross‐communication between antigen‐presenting cells and T cells are involved in the pathogenesis of ITP. Macrophages can polarize into proinflammatory M1 or anti‐inflammatory M2 phenotypes in response to different environmental stimuli, and have diverse immunologic functions. Objectives To investigate the M1/M2 imbalance in ITP and whether high‐dose dexamethasone (HD‐DXM) or all‐trans‐retinoic acid (ATRA) could restore this imbalance. Methods The numbers of M1 and M2 macrophages in the spleens of ITP patients and patients with traumatic spleen rupture were analyzed by immunofluorescence. Monocyte‐derived macrophages were cultured and induced with cytokines and drugs. The expression of M1 and M2 markers and functions of M1 and M2 macrophages before and after modulation by HD‐DXM or ATRA were evaluated with flow cytometry and ELISA. Results There was preferred M1 polarization in ITP spleens as compared with healthy controls. Monocyte‐derived macrophages from ITP patients had increased expression of M1 markers and impaired immunosuppressive functions. Either HD‐DXM or ATRA corrected this imbalance by decreasing the expression of M1 markers and increasing the expression of M2 markers. Moreover, HD‐DXM‐modulated or ATRA‐modulated macrophages suppressed both CD4⁺ and CD8⁺ T‐cell proliferation and expanded CD4⁺CD49⁺LAG3⁺ type 1 T‐regulatory cells. HD‐DXM or ATRA modulated macrophages to shift the T‐cell cytokine profile towards Th2. Treating patients with HD‐DXM or ATRA revealed that macrophages induced from responders showed a predominant M2‐like phenotype and immunosuppressive function. Conclusions Aberrant macrophage polarization is involved in the pathogenesis of ITP. Either HD‐DXM or ATRA is able to correct this imbalance.

In addition to antiplatelet autoantibodies, CD8⁺ cytotoxic T lymphocytes (CTLs) play an important role in the increased platelet destruction in immune thrombocytopenia (ITP). Recent studies have highlighted that platelet desialylation leads to platelet clearance via hepatocyte asialoglycoprotein receptors (ASGPRs). Whether CD8⁺ T cells induce platelet desialylation in ITP remains unclear. Here, we investigated the cytotoxicity of CD8⁺ T cells towards platelets and platelet desialylation in ITP. We found that the desialylation of fresh platelets was significantly higher in ITP patients with positive cytotoxicity of CD8⁺ T cells than those without cytotoxicity and controls. In vitro, CD8⁺ T cells from ITP patients with positive cytotoxicity induced significant platelet desialylation, neuraminidase-1 expression on the platelet surface, and platelet phagocytosis by hepatocytes. To study platelet survival and clearance in vivo, CD61 knockout mice were immunized and their CD8⁺ splenocytes were used. Platelets co-cultured with these CD8⁺ splenocytes demonstrated decreased survival in the circulation and increased phagocytosis in the liver. Both neuraminidase inhibitor and ASGPRs competitor significantly improved platelet survival and abrogated platelet clearance caused by CD8⁺ splenocytes. These findings suggest that CD8⁺ T cells induce platelet desialylation and platelet clearance in the liver in ITP, which may be a novel mechanism of ITP.

Immune thrombocytopenia is an autoimmune disease with abnormal T cell immunity. Cytotoxic T cells, abnormal T regulatory cells, helper T cell imbalance, megakaryocyte maturation abnormalities and abnormal T cell anergy are involved in the pathogenesis of this condition. The loss of T cell-mediated immune tolerance to platelet auto-antigens plays a crucial role in immune thrombocytopenia. The induction of T cell tolerance is an important mechanism by which the pathogenesis and treatment of immune thrombocytopenia can be studied. Studies regarding the roles of the new inducible costimulator signal transduction pathway, the ubiquitin proteasome pathway, and the nuclear factor kappa B signal transduction pathway in the induction of T cell tolerance can help improve our understanding of immune theory and may provide a new theoretical basis for studying the pathogenesis and treatment of immune thrombocytopenia.

Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis. First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls in analysis of the platelet desialylation levels (study I). Next, we conducted an open-label randomized controlled trial (RCT) in which the patients who had severe sepsis with thrombocytopenia (platelet counts ≤50 × 109/L) were randomly assigned to receive antimicrobial therapy alone (control group) or antimicrobial therapy plus oseltamivir (oseltamivir group) in a 1:1 ratio (study II). The primary outcomes were platelet desialylation level at study entry, overall platelet response rate within 14 days post-randomization, and all-cause mortality within 28 days post-randomization. Secondary outcomes included platelet recovery time, the occurrence of bleeding events, and the amount of platelets transfused within 14 days post-randomization. The platelet desialylation levels increased significantly in the 127 septic patients with thrombocytopenia compared to the 134 patients without thrombocytopenia. A platelet response was achieved in 45 of the 54 patients in the oseltamivir group (83.3%) compared with 34 of the 52 patients in the control group (65.4%; P = 0.045). The median platelet recovery time was 5 days (interquartile range 4–6) in the oseltamivir group compared with 7 days (interquartile range 5–10) in the control group (P = 0.003). The amount of platelets transfused decreased significantly in the oseltamivir group compared to the control group (P = 0.044). There was no difference in the overall 28-day mortality regardless of whether oseltamivir was used. The Sequential Organ Failure Assessment score and platelet recovery time were independent indicators of oseltamivir therapy. The main reason for all of the mortalities was multiple-organ failure. Thrombocytopenia was associated with increased platelet desialylation in septic patients. The addition of oseltamivir could significantly increase the platelet response rate, shorten platelet recovery time, and reduce platelet transfusion. Chinese Clinical Trial Registry, ChiCTR-IPR-16008542 .