ST2 was first shown both in vitro and ex vivo to be preferentially expressed on murine Th2 cells (Figure 3; Table 1) expressing predominantly IL-4, IL-5, or IL-10, but not IFN-γ or IL-2 (40, 85). Its expression is independent of IL-4, IL-5, and IL-10, as loss of any of these cytokines does not affect ST2 expression on Th2 cells (40). ST2 expression on Th2 cells is dependent on GATA3 signaling (86) and is enhanced by IL-6, IL-1, TNF-α, and IL-5 (4). Given that ST2 expression in Th2 cells is independent of IL-4 and dependent on GATA3 signaling, it makes sense that ST2 expression occurs late during Th2 differentiation (4). IL-33 stimulation of Th2 cells in vitro increased the amount of IL-5 and IL-13 produced (5). Antigen-specific ST2⁺ Th2 cells were shown to produce more IL-5 and IL-13 compared to non-antigen-specific Th cells and ST2^−/− Th2 cells (87). Interestingly, IL-33 polarization of antigen-stimulated murine and human naïve CD4⁺ T cells leads to high IL-5 production but no IL-4 production, independent of GATA3 and STAT6 induction but dependent on MAPK and NF-κB signaling (88, 89). Adoptive transfer of these cells into naïve IL-4^−/− mice still triggered airway inflammation (88). In vivo administration of IL-33 led to an increase in the number of lymphocytes circulating in the blood and increased type 2 cytokine secretions in the thymus, spleen, liver, and lung (5). IL-33 has also been shown to be a chemoattractant for Th2 cells, as adoptive transfer of Th2 cells into ST2 knockout (KO) followed by IL-33 administration into the footpad of these mice led to the accumulation of the transferred Th2 cells (90). Loss of ST2 on Th2 during infection with the helminthic parasite Nippostrongylus brasiliensis did not affect Th2-mediated clearance of the infection nor was recruitment of Th2 cells in a murine model of asthma dependent on ST2, indicating that ST2 is not necessary for Th2 function (91). Recently, it was shown that human and murine Th2 cells do not produce sST2 in vitro (51).

IL-9-producing Th9 cells are the newest T cell subset to be described, polarized through TGF-β and IL-4 signaling (92, 93). When used separately on naïve T cells, TGF-β alone would cause Treg development, while IL-4 would induce Th2 cell differentiation. It has been found that the PU.1 gene is a Th9-specific transcription factor, which could induce IL-9 production in cells under Th2- or Th9-stimulating condition in vitro (94). Human or mouse PU.1-deficient T cells have diminished IL-9 production. Furthermore, IRF4 binds directly to the IL-9 promoter and is required for the development of Th9 cells, just like PU.1 (95). However, unlike PU.1, IRF4 is also required for the development of other Th cell subsets, including Th2 and Th17 cells (96, 97). Studies have shown that Th9 cells primarily secrete IL-9 to mediate the immune response in several diseases, such as asthma, autoimmune diseases, and parasitic infections (98), and IL-9 is associated with impaired Th1 immune response in patients with tuberculosis (99). Treatment of in vitro polarized human Th2 cells with TGF-β and IL-33 increases their IL-9 and ST2 expressions (100, 101).

ST2/IL-33 signaling in Tregs was first suggested to enhance their protective ability in an experimental colitis model in which IL-33 treatment ameliorated colonic tissue injury and colitis symptoms (41). IL-33 was shown to increase both ST2 and Foxp3 levels and expand Tregs in mice with colitis. ST2/IL-33 signaling in Tregs has also been shown to increase Treg frequency and decrease IL-17 and IFN-γ productions in an experimental autoimmune encephalomyelitis (EAE) model (102, 103). ST2⁺ Treg expansion is helped by IL-33 signaling in DCs, as IL-33 has been shown to stimulate DC production of IL-2, which selectively expands ST2⁺ Tregs (104). In a model of GVHD, treatment of mice daily with IL-33 from 10 days pretransplantation to day 4 posttransplantation enhanced the frequency of ST2⁺ Tregs, which persisted after irradiation, leading to disease amelioration through prevention of T conventional cell accumulation in target GVHD organs (58). Treatment of mice receiving a heart transplant with IL-33 has been shown to prolong graft survival through increase of Treg and myeloid suppressor-derived cell numbers (105, 106). Similarly, mice treated with IL-33 after skin transplantation had increased Treg numbers in the graft, decreased IFN-γ and IL-17 production, increased IL-10 production, and increased skin graft survival (107). This group also showed that ST2/IL-33 signaling can convert Foxp3⁻ CD4 cells into Foxp3⁺ CD4 Tregs in the periphery. We have shown that in a murine model of allogeneic hematopoietic stem cell transplantation (allo-HCT), transplanting ST2 KO Tregs with wild-type (WT) T conventional cells worsens GVHD compared to mice receiving WT T conventional cells and Tregs (51), further indicating the enhanced suppressive effect of ST2⁺ Tregs. Conversely to the enhanced protective effect of Tregs through ST2/IL-33, it has been reported that IRF1 is downstream of MyD88 (108) and negatively regulates Foxp3 transcription (60, 108), although whether ST2/IL-33 signaling increases IRF1 expression, leading to decreased Treg function, has yet to be studied. Given that ST2/IL-33 has been shown to enhance, rather than impair Treg function, upregulation of IRF1 through MyD88 signaling is probably independent of ST2/IL-33. These data show that IL-33 signaling on Tregs increases their immunomodulatory function and could be further studied for their potential clinical benefits in a variety of diseases.

Innate lymphoid cells type 2 were first discovered in the mouse and human mesenteries and found to be lineage marker negative, c-Kit positive, Sca-1 positive, IL-7Rα positive, and ST2 positive (42, 109). These cells have been shown to play a protective role against helminth infection and regulate metabolic homeostasis (110). In humans ST2⁺, ILC2s were later found in the lung and gut (111), and these ILC2s produced IL-5 and IL-13. During ILC2 activation, ST2 is upregulated in a GATA3- and Gfi1-dependent manner (112, 113). Treatment of Rag2 KO mice with IL-33 induced IL-5 and IL-13 production, whereas Rag2 and common gamma chain double KOs, which still have mast cells and basophils (both of which express ST2 and secrete type 2 cytokines), did not increase IL-5 or IL-13 production, indicating that this increase is due to ILC2 stimulation with IL-33 (42). ST2/IL-33 signaling enhancement was shown to expand ILC2s in vivo (42, 114). This group also found that ILC2s are major producers of type 2 cytokines after Nippostrongylus brasiliensis infection. It was also shown using the N. brasiliensis infection model that loss of both IL-33 and IL-25 signaling on ILC2s completely abrogated the early response against this infection due to impaired expansion of ILC2s and lack of IL-13 production, and adoptive transfer of WT ILC2s rescued this phenotype (42). During lung inflammation, ILC2s produce IL-9 (115), and IL-33 can promote cytokine production by ILC2s (116). Recently, it was shown that in a murine eosinophilic airway inflammation model that T-bet regulates IL-9 production by IL-33-stimulated ILC2s (117). ST2/IL-33 signaling in ILC2s is also important for protection against lung infection, as blocking ST2 signaling during influenza infection in mice lowered ILC2 frequency and number in the lung and resulted in diminished lung function, loss of airway epithelial integrity, and impaired respiratory tissue remodeling (118). Histological examination of influenza-infected lungs from anti-ST2-treated mice showed severe damage similar to that seen in a similar experiment where ILC2s were depleted (118). ILC2s have been recently reported to home to the skin in humans, where activation induces upregulation of ST2 (116). ST2/IL-33 signaling of ILC2s in the murine skin has been shown to not only promote atopic dermatitis (AD)-like inflammation (116, 119) but also promote skin wound repair (120). However, overstimulation of ILC2s with IL-33 during tissue remodeling of the liver after chemical injury promoted liver fibrosis (121). Also, signaling through ST2/IL-33 on ILC2s during breast cancer has been shown to promote breast cancer growth and metastasis (122). These data indicate that beneficial or harmful ST2/IL-33 stimulation in ILC2s is dependent on certain disease states.

CD8 T cells have been shown to either express ST2 or produce sST2 (51, 123, 124). Although CD8 T cells express low levels of ST2, loss of either IL-33 or ST2 impaired the CD8 T cell response to LCMV infection (124). ST2/IL-33 signaling has also been shown to enhance CD8 T cell antitumor activity (125). During GVHD, however, IL-33 treatment during peak inflammation significantly increased GVHD severity and mortality in part through increased expansion of Tc1 cells (126). Given that IL-33 can increase type 1 responses when IL-12 levels are high (127), IL-33 treatment during peak inflammation was deleterious in this case.

ST2 has been shown to be expressed on B1 B cells but not B2 B cells, leading to enhanced proliferation capacity and IgM, IL-5, and IL-13 productions both in vitro and in vivo; neutralizing IL-5 almost completely abolished this effect (128). Recent studies have also shown that IL-33 treatment in mice increases circulating IL-10-producing B cells that are neither conventional B1 nor B2 B cells (129). Adoptive transfer of these IL-33-treated, IL-10-producing B cells prevented spontaneous colitis in IL-10^−/− mice without affecting Treg frequency (129).

ST2/IL-33 signaling in murine iNKT cells causes their expansion and activation (130). Mice treated with IL-33 had twice as many iNKT cells in the spleen and liver compared to untreated mice (130). Unexpectedly, ST2 signaling in iNKT cells induced IFN-γ instead of IL-4 upon TCR engagement, which synergized in the presence of IL-12 (47, 130). This effect was also seen in Vα24⁺ human iNKT cells (47). NK cells constitutively express ST2, and ST2/IL-33 signaling increases IFN-γ levels synergistically with IL-12 (47, 130). Loss of ST2 in Ly49H⁺ NK cells did not affect their development but did impair their ability to expand and protect against MCMV (131). These data have yet to translate to human disease.

Although much of the research on ST2/IL-33 signaling in T conventional cells has been devoted to type 2 signaling, recent studies have come out looking at ST2/IL-33 signaling in type 1- and type 17-mediated diseases. Blockade of IL-33 with 200 µg anti-IL-33 every other day from day 0 until day 18 post-MOG_35–55 injection during MOG-induced EAE ameliorated the disease in part through decreased IL-17 and IFN-γ productions, and treatment of 50 µg/kg IL-33 during this same time course enhanced IL-17 and IFN-γ productions (102). However, the amount of IL-33 given here is not physiological, so caution must be advised when interpreting these data. Conversely, another group using the same EAE model found that treatment with 1 µg IL-33 daily from day 12 to day 20 after immunization reduced IL-17 and IFN-γ productions and alleviated the disease (103). Seemingly, timing of ST2/IL-33 signaling affects response, perhaps through differing environments. In a murine model of collagen-induced arthritis, treatment with anti-ST2 antibody reduced both IFN-γ and IL-17 productions (132). In a murine model of rheumatoid arthritis, treatment with an sST2-Fc fusion protein attenuated disease and decreased production of IFN-γ, TNF-α, and IL-6 (133). Recently, we were the first to show that both murine and human Th1 and Th17 cells produce sST2 in vitro and in vivo after allo-HCT (51). Blocking ST2 with a blocking antibody in vivo decreased sST2 production in intestinal T cells 10 days after allo-HCT while maintaining ST2. Recipients of ST2^−/− T cells, compared to WT T cells, showed lower frequencies of T cells expressing the Th1 transcription factor T-bet and the Th17 transcription factor RORγt and their associated cytokines IFN-γ and IL-17, respectively, while increasing the expressions of the Th2 transcription factor GATA3 and the Treg transcription factor Foxp3 and their associated cytokines IL-4 and IL-10, respectively (51). Importantly, anti-ST2 treatment did not lead to loss of immunomodulatory ST2⁺ Tregs but rather maintained them in the intestine. On the basis of our findings, we have suggested that increased sST2 production affects the normal balance of pathogenic Th1/Th17 cells and immunomodulatory Th2/Treg cells by promoting the Th1/Th17 response and dampening the ST2-mediated Th2/Treg response through sequestering IL-33 (51).

We were also the first to demonstrate that CD8 T cells, particularly Tc1 and Tc17 cells but not Tc2 cells, produce significant amounts of sST2 in vitro and after allo-HCT due to alloreactivity (51). sST2 secretion by donor T cells significantly increased as GVHD progressed. Similar to CD4 T cells, blocking ST2 with a blocking antibody decreased sST2 production by Tc1 and Tc17 cells in vivo after allo-HCT (51). Our data indicate that sST2 secretion by Tc1 and Tc17 cells sequester free IL-33, preventing ST2/IL-33-mediated Th2/Treg responses. In patients with early HIV infection, sST2 levels were strongly correlated with CD8 T cell count and their expressions of the activation markers HLA-DR and CD38 (72). However, it is not known if sST2 was produced from the CD8 T cells themselves or if sST2 is only a marker of gut damage and disease progression. While our study was the first to show that preventing sST2 secretion from CD8 T cells prevented disease pathogenesis, further studies are warranted to determine their role in other disease pathogeneses.

Macrophages, mast cells, basophils, eosinophils, and DCs all have been shown to express ST2 (43–46, 134). IL-33 amplifies the expression of M2 markers on murine macrophages (43, 135). Bone-derived human macrophages have been shown to constitutively express both ST2 and sST2; however, skewing these macrophages toward an M2 phenotype using IL-4 and IL-13 increased the expression of ST2 while not affecting sST2 expression (136). ST2/IL-33 signaling has been shown to enhance the activation of macrophages by upregulating the LPS receptor components TLR4 and MD2, soluble CD14, and MyD88 (135).

ST2/IL-33 signaling on both murine and human mast cells has been shown to promote their survival through upregulation of B-cell lymphoma-X large in the peritoneum (137). ST2/IL-33 signaling also promotes mast cell activation and maturation, as IL-33 treatment of CD34⁺ mast cell precursors accelerated their maturation in vitro and induced GM-CSF, IL-5, IL-13, CXCL8, CCL17, CCL22, and CCL2 secretions (138, 139). These cytokine and chemokine secretions may be NFAT and AP-1 signaling dependent (140). It is well documented that mast cells can produce a variety of type 2 cytokines after ST2 signaling (141–143); however, ST2/IL-33 signaling on mast cells during airway inflammation has also been shown to promote a Th17 response (144).

ST2/IL-33 signaling promotes not only type 2 cytokine secretions such as IL-4 and IL-13 but also IL-8 in synergy with IL-3 or Fcε receptor activation on basophils (145). Basophils can also release sST2 after activation via IL-3 and C5a or anti-FcεRIα antibody, while IL-33 prevents sST2 release (145). IL-33 induces the degranulation of eosinophils and production of superoxide (45); controls their responsiveness to Siglec 8 (146); and increases IL-13, TGF-β, CCL3, CCL17, and CCL24 in the lungs during airway inflammation (147). Treatment with anti-ST2 antibodies prevented the upregulation of CD11b and decreased survival of eosinophils (148).

Dendritic cells express low basal levels of ST2 on their cell surfaces (134); however, activation of DCs with rapamycin strongly upregulates ST2 through autocrine IL-1β signaling (149). Treatment of DCs with IL-33 has been shown to increase surface levels of MHC-II, CD40, CD80, CD86, OX40L, and CCR7 (134, 150, 151). ST2/IL-33 signaling in DCs also increases their productions of IL-4, IL-5, IL-13, CCL17, TNF-α, and IL-1β (150). In the presence of naïve CD4⁺ T cells, IL-33-activated DCs induce IL-5 and IL-13 but not IL-4 and IFN-γ from the T cells (134, 151). Interestingly, sST2 has also been shown to be internalized by DCs, suggesting a non-canonical method of action for sST2 (152). It is currently unknown whether sST2 can be internalized by other immune cells. IL-33-activated murine DCs have recently been shown to be required for in vitro and in vivo expansion of ST2⁺ Tregs through DC IL-2 production (104), which could be used for therapeutic benefit against inflammatory diseases through expansion of Tregs both in vitro and in vivo. ST2 expression on host hematopoietic cells, including DCs, and non-hematopoietic cells was not implicated in the severity of GVHD as recipient ST2 KO bone marrow chimeras did not modify GVHD severity (51).

While ST2 has been shown to be present on neutrophils (46, 153), not much is known about the role of ST2 on neutrophils. It has been shown that IL-33-treated murine and human neutrophils do not downregulate CXCR2 induced by the activation of TLR4 through the inhibition of GRK2 (153). IL-33 injected into the ears of mice induced neutrophil recruitment to the skin (154); however, it is not clear if ST2/IL-33 signaling on the neutrophils directly led to their migration.

It is believed that IBD starts with a dysregulated immune response to either food or commensal gut bacteria, leading to the production of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1, and IL-8. Expression of these cytokines along with chemokine release leads to attraction of T cells, specifically type 1 T cells, to the intestines. Continual damage of the gut mucosa by these type 1 cells and other immune cells such as macrophages, neutrophils, and DCs leads to the release of various alarmins and other proteins. sST2 was found to be significantly increased in both the gut mucosa and the serum in both patients and experimental models of IBD (13–16). However, in IBD patients, ST2 expression remained similar to that of healthy patients (13). In the lamina propria of active ulcerative colitis (UC) patients, ST2 predominately came from CD11b⁺ and CD4⁺ cells (14). These findings suggest that increased sST2 production by lymphocytes or the gut mucosa could either lead to development of IBD, particularly UC, or that these proteins are markers for disease severity.

ST2/IL-33 signaling has been shown to enhance epithelial proliferation and mucus production in the gut (5), suggesting that the increase in IL-33 in the colonic mucosa in active UC could be beneficial. However, in multiple mouse models of IBD, use of ST2 KO mice led to amelioration of IBD compared to WT controls. These results were verified using an IL-33 KO. Using bone marrow chimeras, it was shown that ST2 signaling in non-hematopoietic cells was responsible for IBD. This was due to ST2/IL-33 signaling impairing epithelial barrier function and delayed wound healing. Lack of ST2 signaling in hematopoietic cells did not prevent UC development. A ST2 blocking antibody confirmed the findings from the KO experiments (155). Crohn’s disease (CD), however, shows opposite results from UC. In a trinitrobenzene sulfonic acid-induced IBD model, which mimics the pathology of human CD, administration of recombinant IL-33 (rIL-33) into mice ameliorated colonic tissue injury and clinical symptoms (156). Protection was shown to be through upregulation of type 2 cytokines, Foxp3⁺ Tregs, and CD103 DCs, which promote Treg development. In patient colons with active IBD, Treg levels in the lamina propria are increased compared to healthy controls and function normally (157, 158). It has recently been shown that colonic Tregs preferentially express ST2 and that signaling through ST2/IL-33 promotes both Treg accumulation and maintenance in the intestine and enhances their protective function (41). However, treatment with rIL-33 to promote Treg-mediated protection may be time dependent, as rIL-33 treatment at onset of a DSS-induced colitis model exacerbated disease severity. rIL-33 treatment during recovery or chronic phases ameliorated DSS-induced colitis (159). Given these data, selective treatment of ST2⁺ Tregs with IL-33 could provide therapeutic benefits.

Graft-versus-host disease is a common occurrence in patients who undergo allo-HCT as treatment for both malignant and non-malignant diseases of the blood and bone marrow. The pathogenesis of GVHD has been well documented and is now thought to occur in three steps: (1) activation of antigen-presenting cells caused by tissue damage from the conditioning regimen leading to the release of pro-inflammatory cytokines and danger signals, (2) alloactivation of donor T cells leading to their proliferation and differentiation into type 1 and type 17 T cells, and (3) tissue destruction by alloreactive T cells through release of cytolytic molecules leading to donor cell apoptosis, mainly in the mucosal tissues (160). Discovering prognostic and diagnostic biomarkers for GVHD has been successful with sST2 being one of the most validated to date (17–24). Blocking sST2 with a blocking antibody during the peritransplant period decreased GVHD morbidity and mortality in both minor histocompatibility and humanized murine models (Figure 4). Importantly, the ST2-blocking antibody, which inhibits the full length of ST2 and not specifically sST2, maintained protective ST2-expressing T cells while also not impairing the graft-versus-leukemia activity (51), suggesting that addition of anti-ST2 or a ST2 small molecule inhibitor could show efficacy in reducing GVHD-related morbidity and mortality in patients. Using IL-33 as a treatment seems to be time dependent, as injections with IL-33 during the peak inflammatory response in a murine model led to increased morbidity and mortality in mice due to increased migration and increased pro-inflammatory cytokine production (126). IL-33 treatment preconditioning, however, increased the number of ST2⁺ Tregs, which persisted after irradiation in a murine model. This led to decreased GVHD severity and mortality. Adoptive transfer of ST2⁺ versus ST2⁻ Tregs showed that GVHD protection is increased by ST2⁺ and not ST2⁻ Tregs (58). Given that IL-33 is pleiotropic, IL-33 treatment for GVHD seems to be dependent on both timing and the state of inflammation present.

ST2/IL-33 signaling has been implicated in protection from various infections, which could impact the gut. Studies have shown that treatment of mice with rIL-33 led to epithelial cell hyperplasia in the gut along with infiltration of eosinophils and mononuclear cells in the lamina propria (42, 161). These effects are thought to be mediated by IL-13, which becomes overexpressed after IL-33 treatment (5). Treatment of mice with IL-33 after Trichuris muris infection increased parasite clearance through increased Th2 cytokine response (161). Other infections that can impact the gut, including Toxoplasma gondii (162), Leptospira (163), and Pseudomonas aeruginosa (164), have shown that the loss of ST2 or high sST2 levels led to higher morbidity and mortality with increased Th1 cytokine profiles. Recent studies have shown that gut epithelial barrier dysfunction and immune activation independently predict mortality during treated HIV infection (165). A later study showed that patients during the early stage of HIV infection, defined as being within 180 days of the date of infection, had higher levels of sST2 in their plasma and was highly correlated with CD8 T cell count and levels of gut mucosal damage, but not with viral load or CD4 T cell count (72).

sST2 increase has also been implicated during small bowel transplant rejection (25). Patients who had rejection of small bowel transplants had higher serum levels of sST2 during rejection compared to that during rejection-free time points and that rejection increased allograft ST2 expression. An increase in sST2 in the allograft was predicted by Pathway and Network Analysis caused by TNF-α and IL-1β signaling (25). However, these data do not implicate sST2 as a mediator of disease but rather a biomarker of occurring transplant rejection.

Asthma is characterized by varying levels of airway hyperresponsiveness, mucus secretion, bronchoconstriction, and chronic inflammation, affecting 300 million people worldwide (166). ST2/IL-33 signaling in mast cells, ILC2s, eosinophils, basophils, Th2, and Th9 cells drive allergic asthma (141–143, 147, 167–170). Activating ST2 signaling in bone marrow-derived mast cells and basophils in vitro shows strong type 2 cytokine production, including IL-4 and IL-13 (171). Treatment of mice with IL-33 alone induced airway hyperresponsiveness and goblet cell hyperplasia through IL-4, IL-5, and IL-13 induction in the lungs (172). RAG2^−/− mice treated with IL-33 also induce this phenotype, implicating the importance of the innate immune system in generating airway inflammation (171). IL-33 has also been shown to be a chemoattractant for Th2 cells, as injection of IL-33 into the footpad of ST2^−/− mice, which were adoptively transferred with WT polarized Th2 cells led to local accumulation of the transferred Th2 cells (90). After ovalbumin (OVA)-induced acute allergic lung inflammation, levels of IL-33, ST2, and sST2 are significantly increased in the lung (172). While activation of the innate immune system in part through ST2/IL-33 signaling establishes airway inflammation, ST2⁺ T cells maintain this inflammation. Indeed, injecting mice with a ST2 blocking antibody during the resolution phase after OVA-induced allergic inflammation, when Th2 cells but not eosinophils are present in the lung, reduced airway hyperresponsiveness and mucus production (173). Loss of both IL-4 and IL-5 during OVA-induced airway inflammation did not abolish airway hyperreactivity, which was abolished only after anti-CD4 treatment (174), suggesting that ST2/IL-33 signaling in CD4 T cells may be critical for efficient antigen-induced airway inflammation (175). Blockade of either IL-33 or addition of sST2 before OVA-induced allergic airway inflammation showed reduced total cell counts and eosinophil counts in the bronchoalveolar lavage fluid and decreased IL-4, IL-5, and IL-13 (40, 52, 176).

During idiopathic pulmonary fibrosis, patients with stable disease versus healthy controls had similar levels of serum sST2; however, during exacerbations of fibrosis, there was over a sixfold increase in serum sST2 in the exacerbation group compared to both healthy controls and stable disease groups, which correlated with measurements of inflammation (67). Patients with acute respiratory distress syndrome had significantly higher sST2 levels at day 0, which were associated with worse prognosis and mortality (177). Serum levels of sST2 were also increased in patients with chronic obstructive pulmonary disease compared to control patients (178). Patients with moderate or severe H1N1 influenza infection also had significantly increased serum sST2 compared to patients with mild H1N1 infection or rhinovirus infection (179). Idiopathic pneumonia syndrome (IPS) occurs in 5–10% of patients who undergo allo-HCT. In a cohort of 42 patients with IPS without infection, sST2 was significantly higher in the serum of patients with IPS compared to healthy controls and patients with human rhinovirus and parainfluenza occurring at approximately the same time after transplantation (180).

Atopic dermatitis is a Th2-driven disease and patients with AD show higher IgE levels and eosinophilia in the skin and blood (181). ST2/IL-33 signaling has been recently implicated in AD, as transgenic mice expressing IL-33 under the keratin 14 promoter had spontaneous AD-like inflammation (119). This led to increased IL-5 producing ILC2s. Mice receiving topically applied OVA, house dust mites, or staphylococcal enterotoxin B led to upregulation of both sST2 and IL-33 expressions (182). Patients with AD have higher IL-33 expression levels in their skin lesions compared to healthy controls (182). However, in a small cohort of 71 adults and 61 children with AD, serum sST2 levels were not significantly elevated compared to adult controls, in contrast to sST2 expression in patient skin lesions (182, 183). Currently, phase I–II clinical trials are being conducted using novel anti-IL-33 antibodies.

Unlike AD, psoriasis is driven by Th1 and Th17 cytokines (184). However, psoriatic skin still shows increased IL-33 expression compared to healthy skin in patients (154). ST2^−/− mice had reduced cutaneous inflammatory responses compared to WT mice in a phorbol ester-induced murine model of psoriasis (154).

Patients with vitiligo are characterized by the disappearance of their melanocytes. In lesions of patients with vitiligo, both ST2 and IL-33 levels were increased, and serum levels of IL-33 were increased (185). As ST2 signaling in psoriasis and vitiligo is relatively new, not much else has been published as of yet.

Scleroderma is characterized by the fibrosis and hardening of the skin and connective tissues, measured by the modified Rodnan skin score (MRSS) test (186). In a two cohort study, serum sST2 levels were increased in patients with scleroderma compared to healthy controls, which, when combined with Spondin-1, best described longitudinal change in MRSS, using mixed linear models (187). This was validated using three other independent cohorts (187).

Chronic GVHD can affect multiple organs, with skin involvement being one of the most common. In a large study of chronic GVHD, plasma samples were collected from patients at day +100 post-allo-HCT. A four-biomarker panel, which included sST2, correlated strongly with chronic GVHD diagnosis, severity, and non-relapse mortality (21).