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Proc Natl Acad Sci U S A. 2010 Dec 21; 107(51): 22122–22127.
Published online 2010 Dec 6. doi:  10.1073/pnas.1016401107
PMCID: PMC3009768
Cell Biology

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis


Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcγRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

Keywords: immune complex, Fcγ receptor

Rheumatoid arthritis (RA) is an autoimmune disease that results primarily in bone and joint destruction (1). Mitogen-activated protein kinases (MAPKs) are expressed and activated in the RA synovium and have been the focus of drug development programs due to their prominent role in control of cytokines, chemokines, degradative enzymes, programmed cell death, and cell proliferation (24). c-Jun N-terminal kinases (JNK), which belong to the MAPK family, are encoded by three separate loci: Jnk1, -2, and -3. Jnk1 and Jnk2 are ubiquitously expressed, whereas Jnk3 is expressed mainly in the heart, testis, and brain (5). Initially, different JNK isoforms were thought to have largely redundant functions, although they might differ in their substrate preferences (2). However, several nonoverlapping functions were also documented (68). JNK isoforms are highly activated in isolated RA fibroblast-like synoviocytes and in the synovium and play important roles in cytokine production and extracellular matrix regulation by enhancing production of metalloproteinases (MMPs) (911). Yet, in inflammatory arthritis, JNK function remains controversial (10, 12, 13).

A variety of cell types are involved in the pathogenesis of RA and other joint destruction diseases (1). In addition to type A and B synoviocytes, mast cells (MCs) are present in both the normal and inflamed synovial tissue of joints in relatively high numbers (14, 15). Although found throughout synovial tissue, MCs are often located in the vicinity of nerves and around blood vessels, where they are positioned to initiate inflammatory reactions, activate endothelial cells, and recruit other immune and inflammatory cells to the joint. Activated MCs produce an array of proinflammatory and pain mediators, and they can activate other immune system cells (16, 17). Although the role of MCs remains controversial, the number of synovial MCs increases in RA and correlates with disease activity (15). Consistent with their activation in the context of arthritis, granule exocytosis was documented in less than 1% of MCs from normal joint tissue, but was seen in 10–15% of MCs in RA synovium (15). These data are consistent with presence of the contents of MC granules, including tumor necrosis factor (TNF) and IL-17A, in synovial fluid (14, 18). The triggers of synovial MC activation in human arthritis remain speculative, but one plausible mechanism is engagement of receptors for IgG Fcγ receptors (FcγRs), given the prevalence of circulating IgG autoantibodies in RA and their presence in synovial immune complexes (14, 15, 19).

To evaluate the potential influence of JNK in autoantibody-mediated joint disease, we chose the K/BxN serum transfer model (20). Although all murine models of arthritis have limitations, this model has utility in evaluating the effector phase of antibody-mediated arthritis (21). Several studies using this model have demonstrated that immune complexes, FcγRs, complement components, and cytokines have important pathogenic functions (2224). MCs coordinate with neutrophils to amplify joint swelling and disease penetrance in serum transfer arthritis (22, 25, 26). Although activation of MCs is likely to be the initiating event, neutrophils and macrophages also are involved in disease development (26, 27).

Here we show that JNK1, rather than JNK2, is essential for the pathogenesis of inflammatory arthritis and that JNK1 promotes arthritis induction and joint destruction in the K/BxN model. JNK1 deficiency results in diminished IL-1β secretion after FcγR engagement and MC degranulation. These results strongly suggest that JNK1 might play a key role in development of inflammatory arthritis, and therefore JNK1 represents an attractive target for the treatment of such diseases.


JNK1 Plays a Role in Passive Serum Transfer Arthritis.

Passive K/BxN arthritis was studied in WT, Jnk1−/−, and Jnk2−/− mice to evaluate the contribution of JNK1 and JNK2 isoforms to disease development. Clinical arthritis scores and joint swelling were similar in Jnk2−/− and WT mice, but clearly reduced in Jnk1−/− mice (Fig. 1A). Histopathological analysis showed markedly reduced inflammatory cell infiltration, joint destruction, and cartilage damage in Jnk1−/− mice (Fig. S1A). Histological inflammation scores for WT, Jnk1−/−, and Jnk2−/− mice were 4 ± 0, 2.2 ± 0.4, and 4 ± 0, respectively; bone erosion scores were 3 ± 0.2, 1.8 ± 0.4, and 3 ± 0, respectively; and cartilage damage scores were 3.4 ± 0.2, 1.6 ± 0.3, and 3 ± 0.4, respectively (Fig. 1B). JNK1-deficient mice had significantly lower scores for all histological indices compared with WT and JNK2-deficient mice (P < 0.05 by ANOVA with Bonferroni post hoc test).

Fig. 1.
A pathogenic role for JNK1 in passive K/BxN serum transfer arthritis. (A) Clinical arthritis scores and ankle swelling in WT (gray circles, n = 15), Jnk1−/− (black squares, n = 15), and Jnk2−/− mice (black circles, n = ...

To evaluate the influence of JNK deficiency on mRNA expression of selected participants in inflammatory arthritis, we determined the relative expression of IL-1β, IL-6, MMP3, and MMP13 in joints from these mice by quantitative PCR (Q-PCR) on day 10 after serum transfer. The mRNAs of all four mediators were significantly decreased in Jnk1−/− mice, but not in Jnk2−/− mice, compared with WT controls (Fig. 1C). There were no differences seen in TNF or IL-17 expression between the groups (Fig. S1B). Similarly, circulating serum IL-6 (Fig. 1D) and IL-1β protein in paw extracts (Fig. 1E) were lower in Jnk1−/− mice relative to WT or Jnk2−/− mice.

Arthritis Depends on JNK1 in Mast Cells.

To evaluate whether joint inflammation was associated with bone marrow (BM)-derived elements or with connective tissue, BM chimeras were generated by irradiating WT and Jnk1−/− recipients and reconstituting them with Jnk1−/− and WT donor BM, respectively. After 8 wk, the chimeras were injected with pooled K/BxN sera. Development of arthritis was dependent on JNK1 expression in BM-derived cells and not in radioresistant cell types, such as synovial fibroblasts (Fig. 2 A and B). Interestingly, cartilage damage was also reduced in Jnk1−/− mice reconstituted with WT BM, despite similar histological inflammatory cell infiltration in WT mice (Fig. 2 C and D). These results suggest that JNK1 in radioresistant cells contributed to cartilage damage, as previously described (10, 12), but was dispensable for recruitment of inflammatory cells. In addition, IL-1β production in the ankles was significantly greater in mice that received WT BM (Fig. 2 E and F).

Fig. 2.
JNK1 in bone marrow-derived cells is critical for serum transfer arthritis. (A and B) Adult WT and Jnk1−/− mice were irradiated and reconstituted with WT or Jnk1−/− bone marrow (eight mice per group). After 8 wk, the chimeras ...

Because analyses of BM lineage-specific studies demonstrate critical requirements for neutrophils and MCs in K/BxN arthritis (2426), we explored the contribution of JNK1 from these lineages. Prior reports suggested that neutrophils played a dominant role in the pathogenesis of K/BxN arthritis. Jnk1−/− mice had a sufficient number of neutrophils in peripheral blood by flow cytometry (Table S1). To assess the functional role of neutrophils in Jnk1−/− mice, we used a previously published protocol (28) and transferred WT CD45.1+ BM into CD45.2+ Jnk1−/− recipients for the first 4 d of arthritis. The transfer did not recapitulate the arthritis seen in WT controls (Fig. 3A), despite the presence of abundant circulating CD45.1+Gr-1+ cells in the periphery (Fig. S2). These data suggested that JNK1 in neutrophils is not critical for developing arthritis and are consistent with other reports that mature neutrophils have little, if any, expression of JNK1 (29).

Fig. 3.
JNK1 in mast cells is critical for development of serum transfer arthritis. (A) WT neutrophils do not restore arthritis. WT, Jnk1−/−, and Jnk1−/− mice that were i.v. injected each day for 4 d with CD45.1+ congenic BM received ...

We then generated bone marrow-derived MCs (BMMCs) from WT and Jnk1−/− mice with high purity as determined by c-Kit and FcεRI staining (Fig. S3). WT (CD45.1+) and Jnk1−/− BMMCs were engrafted into MC-deficient Pretty2 mice (30). Pretty2 mice have a mutation in kit, lack detectable MCs, and have lower numbers of peripheral granulocytes similar to the W/Wv strain (31) (Fig. S4 and Fig. S5). Both WT and Jnk1−/− BMMC-engrafted mice had microscopically visible MCs in the joint at the time of sacrifice that were not detected in Pretty2 mice, but CD45.1+ cells were not detectable by flow cytometry in the blood (Fig. 3B and Fig. S6). K/BxN serum was administered to engrafted mice to induce arthritis. As shown in Fig. 3C, arthritis severity in Pretty2 mice reconstituted with WT BMMCs was similar to that in control mice, whereas Pretty2 mice reconstituted with Jnk1−/− BMMCs showed arthritis scores intermediate between WT and MC-deficient Pretty2 mice. The histological scores of the Pretty2 mice reconstituted with Jnk1−/− BMMCs were also intermediate between WT and MC-deficient Pretty2 mice (Fig. 3D). Thus, disease development is at least partially dependent on JNK1 in BMMCs.

Decreased Degranulation in Jnk1−/− Mast Cells.

Significant MC degranulation was noted as early as 1 h and even more strikingly at 2 and 24 h after i.p. transfer of K/BxN serum (25). Degranulation preceded the onset of any clinical evidence of inflammation in mice, likely contributing to the initiation of joint inflammation, although MCs continue to degranulate during the later, chronic phase of the disease. Although distribution and number of MCs in nonarthritic joints of Jnk1−/− mice were not different from those in WT mice, on day 10 of serum-transferred arthritis the number of MCs with prominently stained granules was statistically greater in Jnk1−/− mice relative to WT and Jnk2−/− mice, suggesting a role for JNK1 in MC degranulation (see Fig. 4A for representative sections and Fig. 4B for quantification). To examine the capacity of Jnk1-deficient MCs to degranulate in this model, we used a histological approach to reveal MC degranulation in the joints as early as 1 and 16 h after serum transfer. Within 30 min of i.p. K/BxN serum transfer, c-Jun phosphorylation was increased in peritoneal MCs (Fig. 4C). After 1 h, partially degranulated MCs around the joint were visualized at high magnification (1,000×). The number of degranulated MCs was significantly lower in Jnk1−/− ankles (70% ± 8.5% and 40% ± 5.7% for WT and Jnk1−/−, respectively; P < 0.01). At 16 h, the number of intact MCs detected by scanning microscopy was also statistically lower in WT mice (Fig. 4D), suggesting that MCs degranulate less efficiently after K/BxN sera administration in Jnk1−/− mice.

Fig. 4.
Fewer degranulated MCs in Jnk1−/− mice. Ankles from WT and Jnk1−/− mice were prepared for histology staining with toluidine blue. (A) Representative toluidine blue-stained sections on day 10 after serum transfer. Arrows ...

Decreased IL-1β Production by Jnk1−/− BMMCs.

IL-1β secreted by MCs was suggested to be obligate in initiating the passive K/BxN model (32, 33). As IL-1β production was decreased in Jnk1−/− arthritic joints (Fig. 1E), we investigated the impact of JNK1 deficiency on IL-1β processing. In MCs, IL-1β is cleaved to the active form by caspase 1 (3436) and by other proteases such as chymase and tryptase (37). Chymase and tryptase activities were similar between WT and Jnk1−/− BMMCs (Fig. S7 A and B). Bone marrow-derived macrophage (BMDM) stimulation with LPS and ATP resulted in equivalent amounts of IL-1β secretion in WT and Jnk1−/− BMDMs (Fig. S7C). Hence the mechanisms for generating biologically active IL-1β remain intact in Jnk1−/− cells.

Recently, it was shown that MCs contributed to the initiation of joint inflammation through FcγR-induced IL-1β release (33). Despite similar FcγRII/III expression (Fig. S7 D and E), Jnk1−/− BMMCs secreted less IL-1β when stimulated upon FcγR ligation, but not after calcium or FcεRI stimulation compared with WT and Jnk2−/− BMMCs (Fig. 5A). In addition to reduced IL-1β secretion, Jnk1−/− BMMCs expressed lower amounts of IL-1β mRNA than WT cells after FcγR engagement (Fig. 5B).

Fig. 5.
IL-1β secretion through FcγRs is impaired in Jnk1−/− mast cells. BM from WT and Jnk1−/− mice was harvested and cultured with IL-3–rich medium for 4 wk. (A) IL-1β in lysates of WT, Jnk1−/− ...

Effect of JNK Inhibition on K/BxN Arthritis.

We examined the ability of a JNK-specific peptide inhibitor, D-JNKi (38), which targets both JNK1 and JNK2, to inhibit the development of arthritis and ameliorate active joint inflammation. D-JNKi has been reported to have greater selectivity for JNK than SP600125 (39, 40). Importantly, D-JNKi treatment not only prevented the onset of arthritis (Fig. 6A) but also successfully abrogated joint swelling in mice with established disease (Fig. 6B). Treatment with D-JNKi reduced IL-1β and IL-6 mRNA expression in the paws (Fig. 6C). Moreover, D-JNKi inhibited MC degranulation in the joint synovium at 16 h after serum injection (Fig. 6D). Yet, D-JNKi had no effect on disease development in Pretty2 mice (Fig. 6E). These results further indicate that MCs are an important component of the arthritogenic activity of JNK.

Fig. 6.
Injection of a JNK inhibitor prevents and attenuates inflammatory arthritis. (A) WT mice (six per group) were i.p. injected with 150 μL of pooled K/BxN sera on day 0 and treated with control peptide or D-JNKi daily (20 μg/g) starting at ...


Increasing evidence suggests that MCs play critical roles in IgG-dependent tissue-specific autoimmune diseases, including murine models of multiple sclerosis, RA, bullous pemphigoid, and glomerulonephritis (4144). In RA, circulating IgG isotype autoantibodies and immune complexes can activate synovial MCs through FcγRs (19), triggering release of inflammatory cytokines including TNF, IL-1β, and IL-17. However, the molecular events following FcγR ligation leading to degranulation and cytokine release are poorly defined. Our results demonstrate that JNK1 is a critical component of FcγR-induced IL-1β release and that its activation contributes to the clinical severity of inflammatory arthritis. IL-1β has been implicated in promoting a self-perpetuating inflammatory cycle whereby the initial IL-1β release results in secondary production of chemokines and in recruitment of neutrophils that in turn release more cytokines (45).

The JNKs were originally identified by their ability to phosphorylate c-Jun (2, 46, 47) and to stimulate AP-1 transcriptional activity. In addition to c-Jun, the JNKs might have other substrates (48). Although AP-1 activation is likely to contribute to induction of IL-1β transcription (49), a different substrate must account for JNK-mediated induction of MC degranulation. FcγR-deficient mice are resistant to K/BxN-induced arthritis, suggesting that the pathogenic action of anti-glucose-6-phosphate isomerase (GPI) antibodies depends on FcγR activation (22). FcγRs are expressed on MCs, so their activation by GPI–anti-GPI immune complexes could lead to degranulation and the production of inflammatory cytokines. However, whether JNK1 plays a direct role in phosphorylating an element of the FcγR cascade remains to be determined, and other stimuli that might cause MC degranulation such as complement cannot be excluded.

Because BM chimera studies indicated that JNK1 activation in a hematopoetic cell was crucial to the development of arthritis, we considered that other FcγR-bearing cells might be implicated. Neutrophils are critical in the K/BxN passive transfer model (26) and may account in part for the limited response seen in the Pretty2 mice. However, we were unable to detect circulating donor neutrophils after WT BMMC transfer in Pretty2 mice that developed arthritis. In addition, the repletion of WT neutrophils did not recapitulate arthritis in JNK1-deficient mice. Although FcγR expression by neutrophils contributes to the generation of arthritis (28), the paucity of JNK1 reported in mature neutrophils (29) suggested that these cells use signaling pathways that are not entirely similar to MCs. Other cell types might also be involved in the attenuated course of arthritis in JNK1-deficient mice, including macrophages. The role of macrophages in this model remains controversial; however, we found that Jnk1−/− macrophages retained the ability to produce IL-1β. In contrast, diminished IL-1β secretion by JNK1-deficient MCs could explain the reduced joint swelling and histological joint destruction in these mice.

A current strategy for targeted pharmacologic intervention is kinase inhibition. Imatinib mesylate, an orally available tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia and other malignancies (50), reduces clinical swelling and joint destruction in established murine collagen-induced arthritis (51). This drug is a relatively specific inhibitor of several tyrosine kinases, including c-ABL, BCR-ABL, PDGF receptor, and c-Kit (52). Inhibition of c-Kit induced apoptosis of MCs in human tissue and particularly in the inflamed synovium (53). Furthermore, inhibition of c-Kit attenuated cytokine production in synovial tissue (53), and an open label study with the c-Kit inhibitor masitinib suggested that selective MC depletion might be effective in RA (54). These data suggest that MC-targeted therapies could be beneficial in RA and other rheumatic diseases. We also observed that a JNK-inhibiting peptide abrogated joint swelling in established disease, suggesting that JNK is also involved in the progression of arthritis. Future work is needed for identification of all of the mechanisms through which JNK1 contributes to disease progression and maintenance. This study therefore suggests that a JNK inhibitor that decreases MC degranulation, in addition to JNK's previously elucidated functions in cytokine and MMP biosynthesis, could be another attractive therapeutic agent in RA.

Materials and Methods


KRN T-cell-receptor (TCR) transgenic mice were a gift from D. Mathis and C. Benoist (Harvard Medical School, Boston, MA, and the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France). Jnk1−/− and Jnk2−/− mice were previously described (55). Pretty2 mice were generated by N-ethyl-N-nitrosourea mutagenesis and found to have an A-to-T transversion at position 2388 of the Kit gene on chromosome 5, which resulted in the amino acid substitution I787F (30). CD45.1 congenic mice were purchased from The Jackson Laboratory. All mice were in the C57BL/6 background. Mice used in these experiments were 8- to 12-wk-old females. The mice were bred and maintained under standard conditions at the University of California, San Diego, Animal Facility that is accredited by the American Association for Accreditation of Laboratory Animal Care. All animal protocols received prior approval by the institutional review board.

D-JNKi Peptide Treatment.

D-JNKi amino acid peptide, whose sequence is DQSRPVQPFLNLTTPRKPR-PP-RRRQRRKKRG, and a TAT control peptide, sequence PP-RRRQRRKKRG, were were kindly provided by E. Wagner (Centro Nacional de Investigaciones Oncológicas, Madrid). Specific inhibition of JNK activation by D-JNKi has been shown previously (38). D-JNKi or TAT peptides diluted in PBS were injected i.p. at 20 μg/g body weight i.p. daily, starting on day 0 or on day 4 after induction of passive K/BxN arthritis.

Supplementary Material

Supporting Information:


M.G. was supported by the Arthritis Foundation and the Spanish Society of Rheumatology, and M.C. was supported by the Arthritis Foundation. Work in the laboratories of M.K., T.K., and G.S.F. was supported by Grants ES006376, AI61796, and AR47825, respectively, from the National Institutes of Health.


The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1016401107/-/DCSupplemental.


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