TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

Pyrin is an inflammasome sensor that promotes caspase-1–mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (Mefv^V726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.

TNF promotes pyrin expression and inflammasome activation. To investigate the role of TNF signaling in pyrin inflammasome activation, we stimulated WT, Tnf^–/–, and Tnfr1^–/– Tnfr2^–/– BM-derived macrophages (BMDMs) with Clostridium difficile toxin B, a canonical pyrin-activating stimulus (7). BMDMs deficient in TNF signaling (Tnf^–/– and Tnfr^–/–) exhibit reduced inflammasome activation, as assessed by lower caspase-1 cleavage, IL-1β maturation, and lactate dehydrogenase (LDH) release consequent to pyroptotic cell death (Figure 1, A–C, and Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI121372DS1). Pyrin expression was significantly upregulated in response to C. difficile toxin stimuli, and this upregulation was mediated by the TNF/TNFR axis (Figure 1D). To determine whether C. difficile toxin itself induces TNF production, we assessed the level of TNF transcripts and observed upregulation of TNF mRNA in response to the stimuli (Supplemental Figure 1B). TNF mRNA was upregulated even in response to commercially available purified toxin (C. difficile toxin B [TcdB]), in accordance with prior reports (41) (Supplemental Figure 1C). Further, Tnf^–/– and Tnfr^–/– BMDMs responded with lower caspase-1 processing, IL-18 release, and pyroptotic cell death following purified toxin (TcdB) stimuli (Supplemental Figure 1, D–F). These data demonstrate the critical role of TNF signaling in pyrin inflammasome activation.

Figure 1

TNF signaling promotes pyrin expression and inflammasome activation. (A) Caspase-1 processing, (B) IL-1β release, and (C) LDH release in BMDMs in response to C. difficile stimuli for 24 hours. (D) Pyrin expression in BMDMs in response to C. difficile stimuli. (E) Pyrin, NLRP3, and IL-1β expression in BMDMs following TLR stimuli LPS (TLR4), Pam3CSK (TLR1/TLR2), poly(I:C) (TLR3), and gardiquimod (TLR7). (F) Caspase-1 processing and (G) IL-1β release BMDMs in response to LPS priming for 4 hours followed by ATP, nigericin. or silica for 30 minutes, 2 hours, or 12 hours, respectively. (B, C, G) Data are presented as mean ± SEM and are representative of at least 3 independent experiments. ****P < 0.0001 compared with WT, 1-way ANOVA followed by Fischer’s LSD test.

Pyrin upregulation in response to multiple microbial ligands and cytokine stimuli has been reported previously (15). We therefore assessed whether TNF signaling is central to pyrin upregulation in response to other TLR and cytokine stimuli. Pyrin expression was significantly upregulated by multiple inflammatory stimuli, including LPS, Pam3CSK4, polyinosinic:polycytidylic acid (poly[I:C]), and gardiquimod, and this upregulation was significantly lower in the absence of TNF/TNFR signaling (Figure 1E). Expression of NLRP3, another inflammasome sensor, and cytokine IL-1β, on the other hand, were induced in a manner independent of TNF signaling in response to the same stimuli (Figure 1E). Further, NLRP3 inflammasome activation and subsequent IL-1β release in response to canonical NLRP3 triggers ATP, nigericin, and silica were independent of TNF signaling (Figure 1, F and G). We also tested to determine whether activation of other inflammasomes, NLRC4 and AIM2, was affected by TNF signaling. Caspase-1 processing and IL-1β release were similar among WT, TNF, and TNFR-deficient BMDMs in response to NLRC4 triggers Salmonella and Pseudomonas and the AIM2 trigger-transfection of DNA analog poly(deoxyadenylic-deoxythymidylic) (poly[dA:dT]) (Supplemental Figure 2). These data demonstrate that the TNF/TNFR axis is specifically required to promote pyrin inflammasome activation. Similarly to TLR stimuli, TNF directly induced pyrin expression in WT BMDMs (Figure 2A). IFN-β stimuli promoted Tnf upregulation (Figure 2B) and induced pyrin expression via TNF signaling (Figure 2A). The critical role of TNF/TNFR in pyrin expression was additionally observed in peritoneal macrophages under unstimulated conditions and in response to LPS, Pam3CSK4, or IFN-β stimuli (Figure 2C).

Figure 2

Pyrin activation observed in Mefv^V726A/V726A monocytes is promoted by TNF signaling. Pyrin expression in (A) BMDMs and (C) peritoneal cells following TLR and cytokine stimuli (TNF, IFN-β) over 24 hours. (B) Tnf expression in WT BMDMs stimulated with IFN-β. (D and F) Caspase-1 processing, pyrin expression, and (E and G) IL-1β release in monocytes in response to LPS (200 ng/ml) stimuli for 24 hours. (B, E, G) Data are presented as mean ± SEM and are representative of at least 3 independent repeats. ****P < 0.0001 compared with Mefv^V726A/V726A, 1-way ANOVA followed by Fischer’s LSD test.

Next, we assessed whether TNF signaling was also involved in the overt pyrin inflammasome activation observed in Mefv^V726A/V726A cells (10). LPS stimuli induced inflammasome activation in Mefv^V726A/V726A monocytes, as assessed by caspase-1 cleavage and IL-1β release (Figure 2, D–G). Both parameters of inflammasome activation were significantly abrogated in the absence of the TNF signaling axis (Figure 2, D–G). Similar to the observations with BMDMs, pyrin expression in Mefv^V726A/V726A monocytes was also promoted by the TNF/TNFR axis (Figure 2, D and F). Overall, these data highlight a central role for TNF in synergizing with multiple stimuli (microbial and IFN-β) to promote pyrin expression and inflammasome activation.

TNF promotes runting and systemic inflammation in FMF mice. We have previously identified inflammasome-mediated IL-1β production as an instigator of pathology in Mefv^V726A/V726A mice. Alongside IL-1β, levels of TNF were also significantly elevated in the Mefv^V726A/V726A mice in comparison with control Mefv^V726A/+ mice (Figure 3A), which is consistent with previous reports (5). As TNF signaling was involved in pyrin inflammasome activation (Figures 1 and 2), we assessed the contribution of TNF signaling in the FMF disease model by generating Mefv^V726A/V726A mice that lack TNF or its receptors, TNFR1 and TNFR2. Loss of TNF signaling provided significant protection against runting, a trait observed in Mefv^V726A/V726A mice (10) (Figure 3, B and C). Mefv^V726A/V726A mice lacking TNF or both TNFR1 and TNFR2 gained significantly more weight as compared with the Mefv^V726A/V726A mice (Figure 3, B and C).

Figure 3

TNF signaling promotes runting and systemic inflammation in Mefv^V726A/V726A mice. (A) Level of TNF in serum of indicated mice at 8 to 10 weeks of age. (B) Body weights of indicated number of female mice and (C) representative whole-body image of mice at 8 weeks of age. (D) Cytokine levels in serum samples. (A, B, D) Data are presented as mean ± SEM with (A and D) n = 14–30 for each genotype. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 compared with Mefv^V726A/V726A, Student’s t test (A), 2-way ANOVA (B), and Kruskal-Wallis test followed by Dunn’s post test (D).

Chronic inflammation is a major driver of systemic wasting, and increased levels of inflammatory mediators are observed in the serum of Mefv^V726A/V726A mice (5). To assess the role of TNF signaling in promoting systemic inflammation, we assessed the level of cytokines and chemokines in the sera of various strains of Mefv^V726A/V726A mice. Production of certain inflammatory mediators, such as IL-1β, MIP-1α, and GM-CSF, was significantly elevated in Mefv^V726A/V726A mice and blunted in the absence of TNF signaling (Mefv^V726A/V726A Tnf^–/– and Mefv^V726A/V726A Tnfr1^–/– Tnfr2^–/–) (Figure 3D). Other inflammatory mediators, such as IL-6, G-CSF (granulocyte-colony stimulating factor), IL-17, KC, and MCP-1, were significantly higher in Mefv^V726A/V726A mice and not significantly affected by the loss of TNF signaling (Figure 3D). While the genetic loss of IL-1β completely rescued Mefv^V726A/V726A mice from systemic wasting and inflammation (10), loss of TNF significantly reduced the production of specific inflammatory mediators, including IL-1β, and the extent of systemic wasting.

Anemia is observed in patients with FMF (42), and inflammatory cytokines including TNF have been ascribed an inhibitory role in erythropoiesis leading to anemia (43–46). Features of anemia, including lower hematocrit (HCT) and hemoglobin (Hb) levels, were observed in the blood of Mefv^V726A/V726A mice and were significantly affected by loss of TNFRs (Table 1). Further, lower mean corpuscular volume (MCV) and higher red blood cell distribution width (RDW) observed in Mefv^V726A/V726A mice are indicative of anemia associated with iron deficiency (47, 48). These alterations were mildly but significantly restored with the loss of TNF or simultaneous loss of TNFR1 and TNFR2 (Table 1). Overall, these data suggest that the TNF/TNFR axis promotes various features of FMF disease, including systemic wasting, inflammation, and anemia.

Table 1

Modulation in anemia and blood cellular composition by TNF and TNFR signaling in Mefv^V726A/V726A mice

TNF is a critical driver of neutrophilia and granulopoiesis observed in Mefv^V726A/V726A mice. Systemic neutrophilia is one of the hallmarks of FMF (1, 5), and TNF has been shown to directly promote myelopoiesis (49). Neutrophilia, as ascertained by the proportion and number of circulating neutrophils, was significantly reduced in the absence of TNF signaling in Mefv^V726A/V726A mice (Figure 4, A and B, and Table 1). Mefv^V726A/V726A mice further exhibited extramedullary granulopoiesis in the liver (Figure 4C) and spleen (Figure 4D) that was also significantly reduced in the absence of TNF signaling. While loss of TNF signaling did not protect against splenomegaly (Figure 4E), the proportion and number of granulocytes (Figure 4, D and E, and Supplemental Figure 3) in the spleen were significantly reduced in the absence of TNF signaling in Mefv^V726A/V726A mice. Spleens from Mefv^V726A/V726A mice also exhibited altered cellular composition, characterized by loss of lymphocytes (both B and T cells) (Figure 4D and Supplemental Figure 3). Genetic loss of TNF and TNFR markedly rescued the altered cellularity, as the proportion of B and T cells was elevated in Mefv^V726A/V726A Tnf^–/– and Mefv^V726A/V726A Tnfr^–/– mice (Figure 4D and Supplemental Figure 3). These data demonstrate that neutrophilia and extramedullary granulopoiesis in Mefv^V726A/V726A mice are specifically promoted through TNF signaling.

Figure 4

TNF signaling promotes neutrophilia and granulopoiesis in Mefv^V726A/V726A mice. (A) Number of neutrophils (PMN) in blood (/ml) and (B) representative contour plot depicting proportion of PMNs (CD11b⁺Gr1⁺) in blood of indicated mice. Cells were gated on single cells; the percentage of cells identified as neutrophils is noted on each plot. (C) Representative H&E-stained sections of liver tissues. Original magnification, ×20. (D) Cellular composition in spleens of Mefv^V726A/V726A mice. B220, CD3, and Ly6C represent B cells, T cells, and monocytes/granulocytes, respectively. Scale bars: 50 μM. (E) Weight and total number of granulocytes in the spleens of indicated mice. (A and E) Data are presented as mean ± SEM with n = 8–16 for each genotype. *P < 0.05; **P < 0.01; ****P < 0.0001 compared with Mefv^V726A/V726A mice, using Kruskal-Wallis test followed by Dunn’s post test.

Neutrophilia in FMF mice is driven by hematopoietic cells (5), and since TNF is a critical driver of neutrophilia (Figure 4), we assessed whether TNF production by or TNFR signaling within the hematopoietic compartment was required to drive neutrophilia in Mefv^V726A/V726A mice. To address this, we generated BM chimeras with WT mice as recipients and Mefv^V726A/+, Mefv^V726A/V726A, Mefv^V726A/V726A Tnf^–/–, and Mefv^V726A/V726A Tnfr^–/– as donors. Reconstitution of irradiated WT mice with Mefv^V726A/V726A (but not Mefv^V726A/+) BM cells induced neutrophilia (Supplemental Figure 4, A and B). This neutrophilia was significantly reduced in mice reconstituted with TNF-deficient BM cells (Mefv^V726A/V726A Tnf^–/– >> WT), but not TNFR-deficient donor cells (Mefv^V726A/V726A Tnfr^–/– >>WT) (Supplemental Figure 4). These data demonstrate that TNF produced by hematopoietic cells acts on stromal cells to promote neutrophilia in Mefv^V726A/V726A mice.

TNFR1 promotes systemic wasting, anemia, and neutrophilia in Mefv^V726A/V726A mice. TNF is known to signal through both TNFR1 and TNFR2 (44). To assess their relative function in FMF pathologies, we generated Mefv^V726A/V726A mice lacking either TNFR1 or TNFR2. The loss of TNFR1 alone was sufficient to reduce systemic wasting in Mefv^V726A/V726A mice (Figure 5, A and B). Similar to systemic wasting, parameters of anemia — Hb, HCT, MCV and RDW levels — that were altered in the Mefv^V726A/V726A mice were ameliorated by genetic deletion of TNFR1, while TNFR2 was largely dispensable (Figure 5C). Furthermore, deficiency of TNFR1 prevented neutrophilia, while the loss of TNFR2 had no effect (Figure 6, A and B). Extramedullary granulopoiesis in liver and spleen of Mefv^V726A/V726A mice too was mediated specifically through TNFR1 (Figure 6C). While splenomegaly was not significantly rescued by loss of TNFR1 (Figure 6D), the number of granulocytes in spleens of Mefv^V726A/V726A mice was significantly reduced by specific loss of TNFR1 (Figure 6E). Therefore, these pathogenic effects of TNF in Mefv^V726A/V726A mice are mediated specifically through TNFR1 signaling.

Figure 5

TNFR1 signaling promotes runting and anemia in Mefv^V726A/V726A mice. (A) Body weights of indicated numbers of female mice and (B) representative whole-body images of mice at 8 weeks of age. (C) Features of anemia, including Hb, HCT, MCV, and RDW levels in the blood of indicated mice. n = 9–39 per genotype. (A and C) Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001 compared with Mefv^V726A/V726A using (A and C) 1-way ANOVA or Kruskal-Wallis followed by Fisher’s LSD or Dunn’s post test.

Figure 6

TNFR1 signaling promotes neutrophilia and granulopoiesis in Mefv^V726A/V726A mice. (A) Number of neutrophils (PMN) in blood (/ml) and (B) representative dot plot depicting proportion of PMNs (CD11b⁺Gr1⁺) in blood of indicated mice. Cells were gated on single cells; percentage of cells identified as neutrophils is noted on each plot. (C) Representative H&E-stained sections of liver tissues and immunofluorescence for myeloid cells (Ly6C) in the spleen. Scale bars: 50 μM. Original magnification, ×40. (D) Weight and (E) total number of granulocytes in the spleens of indicated mice. (A, D, E) n =6–16 per genotype. ***P < 0.01; **P < 0.01; ****P < 0.0001 compared with Mefv^V726A/V726A by Kruskal-Wallis followed by Dunn’s post test.

TNFR2 signaling is protective against colitis and arthritis in Mefv^V726A/V726A mice. Serosal inflammation, including inflammation in the colon and joints, has been observed in both FMF patients (50) and the murine model of FMF (5). We have previously shown that IL-1β protects against serosal tissue inflammation in Mefv^V726A/V726A mice (10). Since anti-TNF therapies have been used in the treatment of inflammatory disorders, including colitis and arthritis, we theorized that TNF signaling would be particularly important in colon and joint inflammation. The colon tissue was assessed for histological perturbations, and colons from Mefv^V726A/V726A mice exhibited substantial inflammation characterized by immune cell infiltration in both the mucosa and submucosa. While the genetic loss of TNF or TNFR1 provided significant protection against colonic inflammation, the absence of TNFR2 exacerbated inflammation in the colons of Mefv^V726A/V726A mice (Figure 7, A and B). Further, loss of TNFR2 also negated the protection provided by loss of TNFR1, and mice with concomitant loss of both TNFR1 and TNFR2 displayed inflammation comparable to that of Mefv^V726A/V726A mice (Figure 7, A and B).

Figure 7

Serosal inflammation in Mefv^V726A/V726A mice is distinctly mediated by TNFR signaling. (A) Histological analysis of colon tissue in mice. (B) Representative images of H&E staining of proximal colon. Original magnification, ×10. (C) Photograph of mice highlighting ankle joint inflammation in strains of Mefv^V726A/V726A mice. The numbers below each image represent the proportion of mice in which joint inflammation was visibly discernible. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 compared with Mefv^V726A/V726A, 2-way ANOVA followed by Fischer’s LSD test.

In addition to colitis, Mefv^V726A/V726A mice exhibited joint inflammation that was visibly discernible in the hind limbs of the mice (Figure 7C). Ankle inflammation (in the form of joint swelling) was observed in about 50% of Mefv^V726A/V726A mice, 63 % of Mefv^V726A/V726A Tnfr2^–/–, and 53 % of Mefv^V726A/V726A Tnfr1^–/– Tnfr2^–/– mice (Figure 7C). Genetic deletion of TNF or TNFR1 was protective against the joint pathology, with none of the TNF- or TNFR1-deficient Mefv^V726A/V726A mice exhibiting joint inflammation (Figure 7C). These data demonstrate that TNF/TNFR1 signaling promotes colitis and joint inflammation in the FMF model, while TNFR2 signaling is protective. Further, the protection provided by absence of TNFR1 was lost with simultaneous deletion of TNFR2 (Figure 7). Therefore, TNRF1 and TNFR2 function distinctly to alter serosal and systemic inflammation in Mefv^V726A/V726A mice. Given that the loss of TNFR1 does not protect Mefv^V726A/V726A mice lacking TNFR2, the protection conferred by TNFR2 signaling is unlikely to be mediated through sequestration of TNF or inhibition of the pathogenic TNFR1-mediated signal.

One of the major antiinflammatory roles ascribed to TNFR2 signaling includes stability of Tregs (51, 52). TNFR2 agonists have been used as a strategy to boost Treg response (53). We therefore assessed whether loss of TNFR2 affected the proportion of Tregs in Mefv^V726A/V726A mice. The proportion of Tregs was significantly increased in both the spleens and popliteal LNs (pLN) of Mefv^V726A/V726A mice and was reduced with simultaneous deletion of both TNFR1 and TNFR2 (Supplemental Figure 5). The loss of TNFR2 alone, however, did not result in a similar decrease in the proportion of Tregs (Supplemental Figure 5). Within the pLN, the proportion of Tregs was instead significantly enhanced in the absence of TNFR2 (Supplemental Figure 5). Therefore, the proportion of Tregs correlated with the extent of inflammation and was not intrinsically regulated by TNFR2. These data preclude the loss of Tregs as the mechanism for increased colitis and joint inflammation in Mefv^V726A/V726A mice lacking TNFR2.

DS and TDK conceptualized the project. DS, AM, and CG executed the experiments. PV carried out histological assessment. DS conducted data analysis. DS and TDK wrote the manuscript. TDK acquired funding and provided resources and overall supervision.

View Supplemental data

We thank Dan Kastner (NIH) for Mefv^V726A/+ and Mefv^V726A/V726A mice and Nigel Minton (University of Nottingham, Nottingham, United Kingdom) and William A. Petri Jr. (University of Virginia, Charlottesville, Virginia, USA) for providing the C. difficile strains. We also thank Amanda Burton for technical assistance. This study was supported by grants from the US NIH (AR056296, CA163507, AI101935, and AI124346) and the American Lebanese Syrian Associated Charities (to TDK).

Address correspondence to: Thirumala-Devi Kanneganti, Department of Immunology, St. Jude Children’s Research Hospital, MS #351, 262 Danny Thomas Place, Memphis Tennessee 38105-3678, USA. Phone: 901.595.3634; Email: Thirumala-Devi.Kanneganti@StJude.org.

Conflict of interest: The authors have declared that no conflict of interest exists.

License: Copyright 2019, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(1):150–162.https://doi.org/10.1172/JCI121372.

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