Psoriasis is an inflammatory disorder that causes red, flaky patches of skin. The disease affects around 2% of the world’s population, and is most common in people of northern European descent. TNF is one of the key proteins in the development of psoriasis and drugs that inhibit TNF have been very successful in the treatment of this disease. However, these drugs are expensive and for unknown reasons at least 10% of patients do not respond to them.

Attempts to develop better drugs for psoriasis would be assisted by an improved understanding of this disease in terms of the genes and proteins involved. Etemadi et al. set out to obtain a more detailed molecular understanding of this disease by developing new mouse models of the condition. Mice were genetically engineered such that a key gene was deleted specifically from the skin cells that form the main barrier to the environment. These mice demonstrated that defects in skin cells called keratinocytes, rather than defects in the immune response, could lead to a psoriasis-like disease.

Etemadi et al. also showed that the skin cells with this genetic defect die in the presence of TNF and this cell death in mice caused a rapidly-appearing form of psoriasis. However, in the absence of TNF the mice still developed psoriasis, albeit more slowly. In this case, the condition was due to an excessive activation of a protein called NF-κB, which is known to play a role in maintaining balance in the immune system and in psoriasis.

These findings reveal how keratinocytes, cell death and inflammation can directly contribute to psoriasis-like conditions in mice. The next challenge will be to determine whether these findings can be used to help patients with this condition.

TNF Receptor Associated Factor 2 (TRAF2) is an adaptor protein that transduces signals following ligation of certain cytokine receptors including those binding TNF. It was first identified together with TRAF1 as a component of TNF receptor-2 and then TNF receptor-1 (TNFR1) signalling complexes (Rothe et al., 1994; Shu et al., 1996). TRAF2, like most other TRAFs, contains a RING domain, several zinc fingers, a TRAF-N, and a conserved TRAF-C domain which is responsible for oligomerisation and receptor binding through its MATH region (Takeuchi et al., 1996; Uren and Vaux, 1996).

RING domains are nearly always associated with ubiquitin E3 ligase activity (Shi and Kehrl, 2003) and TRAF2 can promote ubiquitylation of RIPK1 in TNFR1 signalling complexes (TNFR1-SC) (Wertz et al., 2004). However TRAF2 recruits E3 ligases such as cIAPs to TNFR1-SC and these have also been shown to be able to ubiquitylate RIPK1 and regulate TNF signalling (Dynek et al., 2010; Mahoney et al., 2008; Varfolomeev et al., 2008; Vince et al., 2009). This makes it difficult to unambiguously determine the role of the E3 ligase activity of TRAF2.

Activation of JNK and NF-κB by TNF is reduced in cells from Traf2^-/- mice while only JNK signalling was affected in lymphocytes from transgenic mice that express a dominant negative (DN) form of TRAF2 that lacks the RING domain (Lee et al., 1997; Yeh et al., 1997). Traf2^-/-Traf5^-/- mouse embryonic fibroblasts (MEFs) have a pronounced defect in activation of NF-κB by TNF, suggesting that absence of TRAF2 can be compensated by TRAF5 (Tada et al., 2001). Although activation of NF-κB was restored in Traf2^-/-Traf5^-/- cells by re-expression of wild type TRAF2, it was not restored when the cells were reconstituted with TRAF2 point mutants that could not bind cIAPs (Vince et al., 2009; Zhang et al., 2010). These data, together with a wealth of different lines of evidence showing that cIAPs are critical E3 ligases required for TNF-induced canonical NF-κB (Blackwell et al., 2013; Haas et al., 2009; Silke, 2011), support the idea that the main function of TRAF2 in TNF-induced NF-κB is to recruit cIAPs to the TNFR1-SC. However, it remains possible that the RING of TRAF2 plays another function, such as in activating JNK and protecting cells from TNF-induced cell death (Vince et al., 2009; Zhang et al., 2010). Furthermore it has been shown that TRAF2 can K48-ubiquitylate caspase-8 to set the threshold for TRAIL or Fas induced cell death (Gonzalvez et al., 2012). Moreover, TRAF2 inhibits non-canonical NF-κB signalling (Grech et al., 2004; Zarnegar et al., 2008) and this function requires the RING domain of TRAF2 to induce proteosomal degradation of NIK (Vince et al., 2009). However, structural and in vitro analyses indicate that, unlike TRAF6, the RING domain of TRAF2 is unable to bind E2 conjugating enzymes (Yin et al., 2009), and is therefore unlikely to have intrinsic E3 ligase activity.

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingolipid mediator that regulates proliferation, differentiation, cell trafficking and vascular development (Pitson, 2011). S1P is generated by sphingosine kinase 1 and 2 (SPHK1 and SPHK2) (Kohama et al., 1998; Liu et al., 2000). Extracellular S1P mainly acts by binding to its five G protein-coupled receptors S1P_1-5 (Hla and Dannenberg, 2012). However, some intracellular roles have been suggested for S1P, including the blocking of the histone deacetylases, HDAC1/2 (Hait et al., 2009) and the induction of apoptosis through interaction with BAK and BAX (Chipuk et al., 2012).

Recently, it was suggested that the RING domain of TRAF2 requires S1P as a co-factor for its E3 ligase activity (Alvarez et al., 2010). Alvarez and colleagues proposed that SPHK1 but not SPHK2 is activated by TNF and phosphorylates sphingosine to S1P which in turn binds to the RING domain of TRAF2 and serves as an essential co-factor that was missing in the experiments of Yin et al. Alvarez and colleagues, observed that in the absence of SPHK1, TNF-induced NF-κB activation was completely abolished.

Although we know a lot about TRAF2, there are still important gaps particularly with regard to cell type specificity and in vivo function of TRAF2. Moreover, despite the claims that SPHK1 and its product, S1P, are required for TRAF2 to function as a ubiquitin ligase, the responses of Traf2^-/- and Sphk1^-/- cells to TNF were not compared. Therefore, we undertook an analysis of TRAF2 and SPHK1 function in TNF signalling in a number of different tissues.

Surprisingly, we found that neither TRAF2 nor SPHK1 are required for TNF mediated canonical NF-κB and MAPK signalling in macrophages. However, MEFs, murine dermal fibroblasts (MDFs) and keratinocytes required TRAF2 but not SPHK1 for full strength TNF signalling. In these cell types, absence of TRAF2 caused a delay in TNF-induced activation of NF-κB and MAPK, and sensitivity to killing by TNF was increased. Absence of TRAF2 in keratinocytes in vivo resulted in psoriasis-like epidermal hyperplasia and skin inflammation. Unlike TNF-dependent genetic inflammatory skin conditions, such as IKK2 epidermal knock-out (Pasparakis et al., 2002) and the cpdm mutant (Gerlach et al., 2011), the onset of inflammation was only delayed, and not prevented by deletion of TNF. This early TNF-dependent inflammation is caused by excessive apoptotic but not necroptotic cell death and could be prevented by deletion of Casp8. We observed constitutive activation of NIK and non-canonical NF-κB in Traf2^-/- keratinocytes which caused production of inflammatory cytokines and chemokines. We were able to reverse this inflammatory phenotype by simultaneously deleting both Tnf and Nfkb2 genes. Our results highlight the important role TRAF2 plays to protect keratinocytes from cell death and to down-regulate inflammatory responses and support the idea that intrinsic defects in keratinocytes can initiate psoriasis-like skin inflammation.

TRAF2 is believed to play a key role in TNF signalling, but this hypothesis has not been tested in all tissues, and there are conflicting data on its role. Some of the strongest evidence from knock-out and dominant negative TRAF2 transgenic mice suggests that loss of TRAF2 delays or reduces TNF-induced NF-κB and JNK and is required to protect cells from TNF-induced death (Lee et al., 1997; Yeh et al., 1997). How TRAF2 might perform these functions is not clear. On the one hand, a ∆RING TRAF2 is unable to protect Traf2^-/-Traf5^-/- cells from TNF-induced death even though it is sufficient to reconstitute TNF-induced NF-κB (Vince et al., 2009; Zhang et al., 2010). This suggests that the E3 ligase activity of TRAF2 is not required for TNF-induced NF-κB but is required to protect cells from TNF-induced death. On the other hand, it has been demonstrated that the RING domain of TRAF2 is atypical and seemingly unable to recruit E2 ubiquitin-conjugating enzymes (Yin et al., 2009). A potential resolution for this conundrum was proposed by Alvarez et al. who suggested that the RING of TRAF2 required a lipid co-factor, S1P, to function as an E3 ligase (Alvarez et al., 2010). However, this solution is problematic because these authors showed that loss of SPHK1, and therefore S1P, prevented TNF-induced ubiquitylation of RIPK1 and TNF-induced activation of NF-κB; yet, neither of these two events depends upon the RING finger of TRAF2 (Vince et al., 2009; Zhang et al., 2010). Another difficulty with the Alvarez interpretation of their data is that Sphk1^-/- mice are viable and relatively normal (Allende et al., 2004), while Traf2 knock-outs on a C57BL/6 background die before or shortly after birth (Yeh et al., 1997) and on a BALB/c background develop severe colitis and die within three weeks after birth (Piao et al., 2011). However, if their hypothesis is correct then the phenotype of the Sphk1-deficient mice should be equal to, if not more severe than, that of Traf2^-/- mice. Two groups have explored the implications of the Alvarez finding further: Adada et al. showed that SPHK1 is required for activation of MAPK p38 but not NF-κB after TNF stimulation (Adada et al., 2013), while Xiong et al. showed that neither SPHK1 nor SPHK2 are required for TNF-mediated activation of NF-κB and MAP kinases in macrophages (Xiong et al., 2013).

To explore this problem we performed a detailed analysis of TRAF2 function using cells from a number of different Traf2^-/-tissues and compared their responses to TNF with Sphk1^-/- cells. Surprisingly, Traf2- or Sphk1-deficient BMDMs activated NF-κB, JNK and ERK like wild-type cells in response to TNF, and were insensitive to TNF-induced cell death. However, Traf2^-/- cells were more sensitive than wild-type cells to Smac-mimetic-induced killing, showing that loss of TRAF2 increases the sensitivity of BMDMs to TNF if cIAPs are absent. There might be two reasons for this extra sensitivity: TRAF2 might recruit other E3 ligases that provide some protection in the absence of cIAPs from TNF-induced killing; alternatively, it has been reported that TRAF2 can K48-ubiquitylate caspase-8 and promote its proteosomal degradation, thereby inhibiting TRAIL-induced apoptosis (Gonzalvez et al., 2012). TRAF2 might therefore play a similar role downstream of TNFR1 in macrophages, leading to more TNF-induced death in the absence of cIAPs.

Because loss of TRAF2 had no noticeable effect on TNF signalling in macrophages, we were unable to compare the role of TRAF2 and SPHK1 in TNF signalling. Therefore, we extended our investigation into the role of TRAF2 and SPHK1 in MEFs, MDFs and keratinocytes. These cells required TRAF2 for full-strength TNF signalling and TRAF2 deficiency made them sensitive to TNF-induced death. However, SPHK1 deficiency did not affect either NF-κB or MAPK activation in these cells and they were resistant to TNF-induced death. Consistent with these data we found that ubiquitylation of RIPK1 upon TNF stimulation was normal in Sphk1 knock-out MDFs but delayed and weakened in Traf2^-/- MDFs. TRAF2 has been shown to ubiquitylate the large subunit of caspase-8 and inhibit FasL or TRAIL-induced apoptotic cell death in human cell lines (Gonzalvez et al., 2012). However, we did not detect any caspase-8 ubiquitylation upon TNF stimulation in MDFs. These data indicate that role of TRAF2 in TNF signalling is cell type-specific. In cell types where TRAF2 is required for TNF signalling our data are in line with earlier studies on Traf2^-/- or dominant negative transgenic mice, because we see defects in JNK activation and delayed NF-κB activation (Lee et al., 1997; Yeh et al., 1997). However, in cell types where loss of TRAF2 results in defective TNF signalling, we were unable to detect any equivalent defect in Sphk1 deficient cells, arguing against the idea that S1P is an essential cofactor required for TNF-induced, TRAF2-dependent, NF-κB.

Studies on TRAF2 deficient B cells revealed a crucial role for TRAF2 in B cell development and examined the consequences of Traf2 deficiency on CD40 and BAFF signalling (Gardam et al., 2008; Hostager et al., 2003). Aside from lymphocytes, however, a physiological role for TRAF2 in cells or tissues has not been well defined. Recent studies suggest that TRAF2 could have a crucial role in adult tissue homeostasis; three-week-old Traf2^-/- mice on the BALB/c background developed spontaneous colitis, and this phenotype was due to the death of the colonic epithelium (Piao et al., 2011). In another study, intraperitoneal injection of Tamoxifen to Traf2^loxp/loxpRosa-Cre-ER^T2 mice induced inflammation in the intestine and mortality after one week (Petersen et al., 2015). However, it is not entirely clear whether these defects are due to the loss of TRAF2 in epithelial cells or hematopoietic cells. Therefore, we specifically targeted Traf2 in keratinocytes and investigated the role of TRAF2 in the epidermis. Keratinocyte-specific Traf2 knock-out mice developed epidermal hyperplasia and severe skin inflammation, leading to noticeable lesions around head and submental area by 6 weeks of age. However, consistent with previous reports (Allende et al., 2004; Xiong et al., 2013), no sign of inflammation was detected in the skin of Sphk1^f/fSphk2^-/-Rosa-Cre-ER^T2 mice following activation of Cre-mediated gene deletion with Tamoxifen (Data not shown). Thus, total lack of SPHK isoenzymes did not phenocopy the skin defects seen in the absence of TRAF2, again arguing against an essential role for S1P in TRAF2's function.

Several mouse models of skin inflammation have been rescued by depletion of TNF (Gerlach et al., 2011; Nenci et al., 2006; Pasparakis et al., 2002). While TNF is a major inflammatory mediator and directly drives production of a host of inflammatory cytokines through TNFR1 signalling, it has been proposed that TNF-induced cell death, specifically necroptosis, might also generate Damage Associated Molecular Patterns (DAMPs) that could activate Toll Like Receptors, or other analogous receptors to indirectly promote inflammatory cytokine production (Gerlach et al., 2011; Pasparakis and Vandenabeele, 2015). The relative contribution of these two pathways to inflammation in vivo, and particularly in human pathology, is still unclear. Keratinocyte hyperplasia in Sharpin^cpdm/cpdm mice can be driven by TNF-induced apoptotic death, because deletion of just one allele of Casp8 or epidermal Fadd deletion markedly ameliorated or prevented the TNFR1-dependent inflammatory phenotype (Kumari et al., 2014; Rickard et al., 2014a). Furthermore, epidermal cFlip (cflar) knock-out causes excessive apoptotic death and an initial wave of very rapid hyperplasia in the epidermis that is rescued by TNF inhibition (Panayotova-Dimitrova et al., 2013). Complicating this picture, caspase-8 deficiency in keratinocytes also causes inflammation in the skin and this is rescued partially by Tnf or Tnfr1 deletion (Kovalenko et al., 2009). However, in this case the inflammation was attributed to constitutive activation of Interferon Regulatory Factor-3 (IRF3), which induces the expression of cytokines and chemokines in the epidermis of casp8 epidermal knock-out independently of TNF (Kovalenko et al., 2009). The skin inflammation of epidermal caspase-8-deficient mice (Weinlich et al., 2013), but not of epidermal cFlip-deficient mice (Panayotova-Dimitrova et al., 2013), is completely rescued by loss of RIPK3. Therefore, Weinlich et al. suggested that necroptosis is the cause of inflammation in the epidermal casp8 knock-out. Similarly, Fadd^EKO, Ripk1^EKO and Ripk1^-/- mice develop skin inflammation that has been attributed to RIPK3-dependent necroptosis, highlighting the importance of this pathway in the skin (Bonnet et al., 2011; Dannappel et al., 2014; Dillon et al., 2014; Rickard et al., 2014b). In our model, TNF deficiency only delayed the Traf2^EKO skin phenotype and did not rescue it completely, and inflammation induced by loss of TRAF2 was not prevented by loss of the necroptotic effector MLKL. This was consistent with our analyses on the type of TNF-induced cell death in Traf2^-/- keratinocytes, which was predominantly apoptotic. Therefore, we have crossed Traf2^EKO to Mlkl^-/-Casp8^-/- mice and rescued the early TNF-dependent skin inflammation. Unfortunately, we were unable to age these mice more than 15 weeks, as they developed lymphadenopathy, and we could therefore not examine the effect of Mlkl^-/-Casp8^-/- on the late onset inflammation in the skin. Recently, it has been shown that apoptotic cells could also release DAMPs such as ATP (Poon et al., 2014), and our results support the idea that excessive apoptosis can be inflammatory.

Although the microscopic phenotypes of Traf2^EKO or Traf2^EKOTnf^-/- were similar to human psoriatic lesions, we are not sure whether the infiltration of the immune cells entirely resembles human psoriasis. In our models we observed infiltration of neutrophils and IFNγ-producing CD4⁺ T cells to the skin, which is similar to human psoriasis. However, dermal dendritic cells, macrophages, other subtypes of T helper cells (Th2 and Th17) and cytotoxic T cells have also been reported to have essential roles in initiation and development of psoriasis (Nestle et al., 2009). More investigation about the involvement of different immune cells in different stages of the disease is clearly warranted.

While Tnf deficiency delayed the appearance of the inflammatory skin phenotype in Traf2^EKO mice, at later time points the epidermis thickened and there was a leukocyte infiltration. Because Traf2 deficiency is specific to keratinocytes this implies that there are one or more keratinocyte-intrinsic factors that either promote proliferation and attract inflammatory cells to the skin or attract inflammatory cells which promote keratinocyte proliferation. One possibility is that the constitutive non-canonical NF-κB signalling observed in Traf2^EKOTnf^-/- keratinocytes promotes their proliferation. However, in contrast to Traf2^-/- lymphocytes (Gardam et al., 2008), proliferation of Traf2^EKOTnf^-/- keratinocytes in culture was not altered compared to controls. This suggests that epidermal hyperplasia in the Traf2^EKOTnf^-/- mice is not the result of an intrinsic growth advantage of Traf2^-/- keratinocytes. IL-17 plays an important role in inflammatory diseases and monoclonal antibodies targeting IL-17 such as secukinumab and ixekizumab are performing well in psoriasis patients (Tse, 2013). These successes indicate that IL-17 plays an important role in human psoriasis and it has been shown that IL-17 can induce proliferation of keratinocytes in vivo (Ha et al., 2014). TRAF3 interacting protein 2 and TRAF3 have been linked to IL-17 signalling (Qian et al., 2007; Zhu et al., 2010) where TRAF3 negatively regulates IL-17 receptor signalling. We therefore considered that loss of TRAF2 might have a similar effect to loss of TRAF3 and that IL-17 might promote keratinocyte proliferation in TRAF2-deficient keratinocytes. However, in our experiments, IL-17 did not increase Traf2^EKO/EKOTnf^-/- keratinocyte proliferation compared to Traf2^EKO/+Tnf^-/- cells in vitro and loss of TRAF2 had no impact on IL-17-mediated activation of NF-κB and p38 in keratinocytes. While this does not exclude a role for IL-17 in the psoriasis-like skin phenotype observed in Traf2^EKO or Traf2^EKOTnf^-/- mice, we hypothesized that Traf2^EKOTnf^-/- keratinocytes produced other factors to recruit inflammatory cells to the skin.

We therefore analysed and compared supernatants from Traf2^EKO/EKOTnf^-/- and Traf2^EKO/+Tnf^-/- keratinocytes using Mass Spectrometry, Western blot and ELISA. However, we were unable to detect cytokines such as IL-6, IL-23, IL-24, IL-33, TSLP, IL-18, MCP-1 and GM-CSF using these methods (Data not shown). This failure might be due to low levels of secretion of these factors by keratinocytes maintained in serum-free media, so we investigated the transcription of inflammatory genes. At the mRNA level, several inflammatory genes were highly elevated in Traf2^EKO/EKOTnf^-/- compared to Traf2^EKO/+Tnf^-/- keratinocytes, and many of these, such as M-CSF and IL-23, have been implicated in the development of inflammatory diseases (Nair et al., 2009; van Nieuwenhuijze et al., 2013; Yoshiki et al., 2014).

Depletion of non-canonical NF-κB signalling prevents early lethality in Traf2^-/- mice (Lin et al., 2011; Vallabhapurapu et al., 2008) but did not rescue the Traf2^EKO skin phenotype in our model. Surprisingly, the inflammatory lesions appeared with a different pattern in Traf2^EKONik^aly/aly and the onset of inflammation was even earlier than in Traf2^EKO mice. This could be either due to the susceptibility of Nik^aly/aly to autoimmunity that is exacerbated by the loss of TRAF2 or there could be another unknown pathway inhibited by TRAF2 that is worsened by NIK mutation. In Traf2^EKONfkb2^-/- animals, the onset of inflammation was similar to Traf2^EKO mice, but the development of disease was slightly slower and mice survived marginally longer.

These data show that TNF-dependent cell death, but not non-canonical NF-κB, is a driver of the early inflammation in Traf2^EKO mice. Constitutive activation of non-canonical NF-κB in Traf2^EKOTnf^-/- mice might, however, be responsible for the later onset skin disease that developed in these Tnf-deficient mice (Figure 11). To test this, we deleted both Tnf and Nfkb2, which completely rescued the skin inflammation in Traf2^EKO mice. These data provide insights into the mechanism of initiation and development of inflammatory skin disease that may be important to further understanding of diseases such as psoriasis. Moreover, our findings provide further evidence that TNF-induced apoptosis can play a role in inflammatory skin disease and indicate that defects in keratinocytes themselves can initiate TNF-dependent and -independent inflammation. Importantly, we have shown that non-canonical NF-κB signalling can be the driver of inflammation in epithelial cells. This observation might be relevant to human psoriasis because it has been reported that the levels of TWEAK and its receptor Fn-14 are elevated in human psoriatic lesions (Cheng et al., 2015), and it is well established that TWEAK/Fn14 signalling induces degradation of TRAF2 and activation of non-canonical NF-κB signalling (Saitoh et al., 2003; Vince et al., 2008). Thus, our results suggest that inhibition of non-canonical NF-κB signalling might be beneficial in chronic inflammatory disease together with TNF inhibitors.

Figure 11

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Author details

1. Nima Etemadi

   1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia
   3. Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
   4. School of Cancer Medicine, La Trobe University, Heidelberg, Australia

   Contribution

   NE, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-7137-1373

2. Michael Chopin

   1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia

   Contribution

   MC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

3. Holly Anderton

   1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia

   Contribution

   HA, Designed and performed experiments, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The author declares that no competing interests exist.

4. Maria C Tanzer

   1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia

   Contribution

   MCT, Designed and performed experiments, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

5. James A Rickard

   1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
   2. Department of Medical Biology, University of Melbourne, Parkville, Australia

   Contribution

   JAR, Designed and performed experiments, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

6. Waruni Abeysekera

   Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

   Contribution

   WA, Analyzed data, provided helpful suggestions and discussions, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

7. Cathrine Hall

   Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

   Contribution

   CH, Designed and performed experiments, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The author declares that no competing interests exist.

8. Sukhdeep K Spall

   Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

   Contribution

   SKS, Designed and performed experiments, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The author declares that no competing interests exist.

9. Bing Wang

   Center for Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

   Contribution

   BW, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The author declares that no competing interests exist.

10. Yuquan Xiong

    Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States

    Contribution

    YX, Analyzed data, Provided helpful suggestions and discussions, Acquisition of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

11. Timothy Hla

    Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States

    Contribution

    TH, Analyzed data, Provided helpful suggestions and discussions, Acquisition of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

12. Stuart M Pitson

    Centre for Cancer Biology, SA Pathology, Adelaide, Australia

    Contribution

    SMP, CSB, Analyzed data, Acquisition of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

13. Claudine S Bonder

    Centre for Cancer Biology, SA Pathology, Adelaide, Australia

    Contribution

    SMP, CSB, Analyzed data, Acquisition of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

14. Wendy Wei-Lynn Wong

    Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

    Contribution

    WW-LW, Analyzed data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The author declares that no competing interests exist.

15. Matthias Ernst

    1. Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
    2. School of Cancer Medicine, La Trobe University, Heidelberg, Australia

    Contribution

    ME, Had significant input on conception and design of the revised manuscript after the first submission, Conception and design, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

16. Gordon K Smyth

    1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    2. Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia

    Contribution

    GKS, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0001-9221-2892

17. David L Vaux

    1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Contribution

    DLV, SLN, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

18. Stephen L Nutt

    1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Contribution

    DLV, SLN, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-0020-6637

19. Ueli Nachbur

    1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Contribution

    UN, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

20. John Silke

    1. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    2. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Contribution

    JS, Analyzed data, Provided helpful suggestions and discussions, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    j.silke@latrobe.edu.au

    Competing interests

    The author declares that no competing interests exist.

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