ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production

Xichun Xia; Leqing Zhu; Miaomiao Xu; Zhiwei Lei; Hai Yu; Guangqiang Li; Xiao Wang; Hongling Jia; Zhinan Yin; Fang Huang; Yunfei Gao

doi:10.1016/j.ymthe.2024.03.007

. 2024 Mar 7;32(5):1561–1577. doi: 10.1016/j.ymthe.2024.03.007

ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production

Xichun Xia ^1,^3,^4,⁹, Leqing Zhu ^5,⁹, Miaomiao Xu ^3,^4,⁹, Zhiwei Lei ⁶, Hai Yu ⁷, Guangqiang Li ³, Xiao Wang ³, Hongling Jia ⁸, Zhinan Yin ^3,^4,^∗, Fang Huang ^4,^∗∗, Yunfei Gao ^2,^3,^∗∗∗

PMCID: PMC11081937 PMID: 38454607

Abstract

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.

Keywords: ANKRD22, dendritic cells, NIK, IL-23, skin inflammation, inflammation resolution, NF-κB pathway, ubiquitination, γδ T17, Psoriasis

Graphical abstract

Xia and colleagues described ANKRD22 as a novel endogenous orchestrator mediating inflammation resolution in psoriasis. ANKRD22 interacts with NIK and assists ubiquitination-mediated degradation of NIK, thereby overwhelming TNFRII-NIK-meditated noncanonical NF-κB pathway activation and IL-23 production. These findings suggest that ANKRD22 may have potential as a therapeutic drug for psoriasis.

Introduction

Inflammation is a very common and important basic pathological process, which is a defense response of the organism against harmful stimuli from the internal and external environments. Inflammatory cytokines and chemokines produced by innate immune cells play a key role in the recruitment and activation of inflammation-associated effector cells.¹ However, excessive production of inflammatory factors will lead to immune dysfunction and may induce autoimmune diseases.² Psoriasis is one such chronic inflammatory skin disease, affecting ∼2%–3% of the population worldwide.³ The etiology of psoriasis is multifactorial, and it is characterized by epidermal hyperplasia and sustained skin inflammation. In the context of psoriasis, inflammation resolution is particularly important because chronic inflammation is a key driver of psoriasis-related comorbidities, and persistent inflammation can lead to tissue damage and exacerbation of the disease.⁴ The interleukin (IL)-23/IL-17 axis plays a fundamentally critical role in the development of both the cutaneous and the articular clinical features associated with psoriasis.⁵ Therefore, exploring endogenous orchestrators that promote inflammation resolution against IL-23 in psoriasis is crucial and can provide new insights and targets for the treatment of psoriasis.

Ankyrin Repeat Domain 22 (ANKRD22), containing 191 amino acids, is an ankyrin repeat (AR)-containing protein with 4 copies of the motif. Although ANKRD22 plays important roles in cancer development and progression,⁶^,⁷ the definite function of ANKRD22 is barely comprehended in autoimmunity and chronic inflammation. Data derived from a public gene database shows high mRNA expression of ANKRD22 in normal human skin tissue. Transcriptomes of psoriatic skin lesions suggest a potential pathogenic linkage between ANKRD22 and psoriasis.⁸ In addition, emerging evidence shows that AR-containing proteins were associated with the risk of developing psoriasis, and some of them had been implicated in modulating the IL-23/IL-17 axis.⁹^,¹⁰^,¹¹ However, the specific role of ANKRD22 in regulating inflammation resolution against IL-23 in psoriasis has not been thoroughly investigated.

In our present study, we have provided compelling evidence that ANKRD22 serves as an endogenous negative regulator of psoriasiform skin inflammation. Specifically, it plays a crucial role in inflammation resolution against IL-23 by functioning as a negative feedback regulator targeting accumulated nuclear factor (NF)-κB inducing kinase (NIK). Interestingly, subcutaneous administration of an adeno-associated virus (AAV) carrying an ANKRD22-overexpression vector effectively expedited the resolution of psoriasiform skin inflammation. These findings suggest that ANKRD22 may have potential as a therapeutic protein drug for the treatment of psoriasis.

Results

ANKRD22 acts as an endogenous suppressor of psoriasiform skin inflammation

To analyze ANKRD22 transcripts in mouse skin, we observed that ANKRD22 expression distributed throughout the dermis (Figure 1A) and was higher in hematopoietic (CD45⁺) cells sorted from dermis (Figure 1B). As expected, ANKRD22 was practically undetectable in the skin of ANKRD22-deficient (ANKRD22-knockout [KO]) mice (Figures 1A and 1B). Nevertheless, ANKRD22-KO mice did not show any significant differences compared to their wild-type (WT) littermates (Figure S1), suggesting no spontaneous effect of ANKRD22 deletion on skin homeostasis. ANKRD22 expression was continuously reduced in CD45⁺ cells until day 7 during imiquimod (IMQ)-induced psoriasis-like disease progression, but increased again on day 10, when psoriasiform inflammation resolved (Figure 1C). Given the inverse pattern of ANKRD22 expression and psoriasiform inflammation, we hypothesized that ANKRD22 was implicated in the regulation of psoriasis pathogenesis. To this end, ANKRD22-KO mice and WT controls were topically subjected to IMQ cream on their back skin for 5 consecutive days. We found that ANKRD22-KO mice were more susceptible to IMQ-induced psoriasis-like disease, as was evident by more severe scaly skin, epidermal hyperplasia, and higher Psoriasis Area and Severity Index (PASI) scores (Figures 1D–1F). This phenotype was associated with an increase in the percentage and number of neutrophils in the skin (Figure 1G). In addition, ANKRD22-KO mice showed significantly aggravated splenomegaly (Figure 1H) and body weight loss (Figure 1I). These findings suggested that ANKRD22, highly expressed in dermal immune cells, acted as an endogenous suppressor of IMQ-induced psoriasiform skin inflammation.

Dysregulation of the cutaneous γδ T17 differentiation caused by ANKRD22 deletion in a cell-extrinsic manner

Compared to WT mice, ANKRD22-KO mice exhibited significantly increased expression of cytokines, including IL-1β, IL-6, IL-23A, IL-17A, IL-17F, and tumor necrosis factor α (TNF-α) in the skin, at both mRNA and protein levels, along with decreased IL-10 and unchanged IL-4 (Figure 2A). The main cellular source of IL-17A in the skin of WT and ANKRD22-KO mice treated with IMQ was found to be dermal γδ T cells (Figure 2B). The percentage of dermal γδ T17 cells was significantly higher in ANKRD22-KO mice (Figure 2C). However, the IL-17A production in T helper cell (Th)17 cells did not increase in the skin from ANKRD22-KO mice (Figure S2A). Blocking IL-17 significantly eliminated the differences in the number and proportion of neutrophil infiltration in the skin between WT and ANKRD22-KO mice (Figure S2B). These results indicated that ANKRD22 deficiency aggravated γδ T17 cell-mediated psoriasiform inflammation. To confirm whether ANKRD22 deficiency-mediated aggravation of psoriasiform inflammation was due to its direct function in γδ T cells, naive γδ T cells from WT and ANKRD22-KO mice were adoptively transferred to Tcrd^−/− mice, respectively, and these mice were exposed to IMQ. The mice that received WT naive γδ T cells showed aggravated clinical and pathological features of IMQ-induced psoriasis-like disease (Figure 2D), including increased PASI scores (Figures 2E and S2C) and acanthosis (Figure 2F), exacerbated splenomegaly and body weight loss (Figures 2G and 2H), elevated percentage and number of dermal neutrophils and γδ T17 cells (Figure 2I), as well as cytokine production (Figure S2D). Surprisingly, the mice that received naive γδ T cells from ANKRD22-KO mice showed pathological changes similar to those that received naive γδ T cells from WT (Figures 2D–2I, S2C, and S2D). Moreover, naive γδ T cells from ANKRD22-KO mice showed comparable IL-17 production to that from WT (Figure S2E), both at mRNA and protein levels of IL-17A and IL-17F (Figure S2F), when exposed to the γδ T17 differentiation condition in vitro. The transcription factor RORγt, required for the differentiation of IL-17-producing cells, also displayed no visible alterations between γδ T17 differentiating cells from WT and ANKRD22-KO mice (Figure S2G). These results strongly suggested that ANKRD22 in γδ T cells was not the critical pathogenic factor for psoriasiform skin inflammation.

Dendritic cell (DC)-intrinsic ANKRD22 ablation predominantly contributes to aggravated psoriasiform skin inflammation

Given that DCs were the dominant cell expressing ANKRD22 in skin (Figure S3A) and play a pivotal role in dermal γδ T17 differentiation, we next explored whether ANKRD22 could directly target DCs to regulate psoriasiform inflammation. To this end, CD11c-DTR/GFP transgenic mice were injected intraperitoneally with diphtheria toxin (DT) to specifically deplete CD11c⁺ cells, and then adoptively transferred with bone marrow-derived DCs (BMDCs) from WT or ANKRD22-KO mice, respectively (Figure 3A). The abolishment and reconstruction of dermal CD11c⁺ cells were confirmed by flow cytometry (Figure S3B). Abolishing DCs conferred resistance to IMQ-induced psoriasis-like disease, whereas this phenotype was relapsed by transferring WT-BMDCs, shown by aggravated clinical and pathological characteristics (Figures 3B–3I and S3C). However, mice that received ANKRD22-KO BMDCs were predisposed to be more sensitive to IMQ-induced psoriasiform inflammation than those that received WT BMDCs (Figures 3B–3I and S3C), which recapitulated the phenotype in mice with a global KO of ANKRD22. Furthermore, the differentiation of γδ T17 cells was significantly reinforced in cocultured naive γδ T cells with BMDCs from KO mice rather than BMDCs from WT mice, although the differentiation of γδ T1 cells was not altered (Figure S3D). The classical delayed-type hypersensitivity model revealed no notable disparities in cutaneous inflammation, even during the resolution phase, between ANKRD22-KO mice and WT mice (Figures S4A–S4E). Therefore, DC-specific ANKRD22 depletion predominantly contributed to γδ T17 cell-mediated psoriasiform pathology.

DC intrinsic ANKRD22 ablation predominantly contributes to aggravated psoriasiform skin inflammation

(A) Schematic diagram of DT treatment for depletion of CD11c-expressing DCs in CD11c-DTR mice and adaptively transferred with PBS or BMDC from WT (WT-DC) and KO (KO-DC) mice to these mice undergoing exposure to IMQ (n = 5). (B–F) Representative phenotypic presentation and histologic sections (H&E staining) of skin lesions (B) (scale bars, 100 μm), PASI scores (C), acanthosis (D), splenomegaly (E), and body weight (F) were recorded. (G) Flow cytometry and statistical analysis of the percentage and number of dermal neutrophils (gated on CD45⁺CD90.2^– lymphocytes) and IL-17A⁺γδ T cells (gated on CD3⁺TCR γδ⁺ cells). (H and I) Relative mRNA expression (H) and protein levels (I) of IL-1β, IL-6, IL-23A, IL-17A/F, and TNF-α in skin. Data are represented as the mean ± SD and representative of 3 independent experiments with consistent results. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. (C), (D), and (F–I) 1-way ANOVA test.

ANKRD22 deletion facilitates psoriasiform inflammation by promoting DC-derived IL-23 production

To understand how DC-specific ANKRD22 regulates the development of psoriasiform inflammation, we stimulated BMDCs from WT and ANKRD22-deficient mice with IMQ, and analyzed their gene expression through RNA sequencing (RNA-seq). Overall, by pairwise comparison, 1,395 differentially expressed genes (DEGs) were significantly upregulated, whereas 839 were significantly downregulated (Figure S5A). In the Gene Ontology annotation analysis, 231 DEGs were involved in the immune system process of the biological process group (Figure S5B). Consistent with the in vivo phenotype, the proinflammatory cytokine Il23a, a well-characterized Th17 or γδ T17 differentiation-related gene, was selectively elevated in ANKRD22-KO BMDCs stimulated with IMQ (Figure 4A). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of 231 DEGs revealed that the major biological processes altered in ANKRD22-KO BMDCs were associated with Th cell polarization and autoimmune disease (Figure 4B). Direct ex vivo assay confirmed that ANKRD22 deficiency led to a higher expression and production of IL-23A in BMDCs (Figure 4C) or dermal DCs (Figure 4D) after IMQ stimulation. However, ANKRD22 deficiency had no obvious influences on expression and production of the other proinflammatory cytokine genes (Il1b, Il6, Il12a, and Tnfa) in these cells (Figures S5C and S5D). In addition, the production of IL-23A was drastically enhanced in ANKRD22-KO BMDCs (Figure 4E) or dermal DCs (Figure 4F) in response to CpG stimulation, but not lipopolysaccharide (LPS). These findings suggest that ANKRD22 deficiency specifically increases the expression of IL-23A in a Toll-like receptor (TLR)7/9-dependent manner. To evaluate the contribution of IL-23A to ANKRD22-KO-mediated psoriasiform inflammation, we used an antibody neutralization approach with an IL-23 p19-neutralizing antibody. Injection of anti-p19 not only profoundly attenuated the progression of psoriasiform inflammation in WT mice (Figures 4G–4K and S6A–S6D) but it also abolished the differences in clinical and pathological features between WT and ANKRD22-KO mice (Figures 4G–4K and S6A–S6D). Moreover, IL-23-induced psoriasis-like skin inflammation was comparable between WT and KO mice (Figures 4L–4N and S7A–S7C). These findings highlighted a crucial role of IL-23 in mediating the psoriasiform inflammation caused by ANKRD22 deficiency.

Excessive noncanonical NF-κB activation caused by ANKRD22 deficiency is essential for IMQ-stimulated IL-23 induction

NF-κB signaling plays a crucial role in regulating IL-23 induction in DCs in response to pathogens via two pathways: the canonical and the noncanonical. ANKRD22 deficiency led to excessive activation of a noncanonical NF-κB pathway in BMDCs with IMQ stimulation, as evidenced by enhanced generation of p52 and RelB (Figure 5A). The same effect was also observed in dermal DCs isolated from ANKRD22-KO mice primed with IMQ (Figure 5B). Notably, IMQ or CpG stimulation led to higher levels of p52 and RelB translocation to the nucleus in ANKRD22-KO BMDCs compared to WT cells (Figure 5C). However, ANKRD22 deficiency had no impact on the generation of p50 (Figures 5A and 5B) or nuclear translocation of c-Rel, p50, and p65 (Figure 5C), as well the early phase activation of canonical NF-κB signaling events, including phosphorylation of IκBα and p65 (Figure 5D). In contrast, ANKRD22 deficiency promoted the early phase activation of the MAP kinases (MAPKs) signaling pathway, including three families: ERK, JNK, and p38 (Figure S8A), and naturally led to elevated levels of c-Jun translocation to the nucleus in BMDCs stimulated with IMQ (Figure 5C). Although MAPKs are the major signaling pathways activated by the TLRs, ANKRD22 deficiency had no effect on IMQ-mediated activation of TLR7, manifested by comparable endosomal pH value (Figure 5E) and the cleaved-TLR7 fragment (Figure 5F). Together, these results indicated that ANKRD22 deficiency in DCs promoted IMQ-induced activation of the noncanonical NF-κB pathway and the MAPK signaling pathway. Chromatin immunoprecipitation (ChIP)-PCR assay demonstrated that ANKRD22 deficiency specifically enhanced the recruitment of RelB and p52 to the Il23a promoter following IMQ stimulation (Figure 5G), rather than c-Jun, c-Rel, p50, and p65 (Figure S8B). Administration of SN52, an inhibitor that blocks the nuclear translocation of p52-RelB heterodimers (Figure 5H), significantly impaired the effect of ANKRD22 deficiency on IL-23A hyperproduction (Figure 5H), but not MAPKs inhibitors (Figure S8C). These findings collectively indicated that excessive noncanonical NF-κB activation caused by ANKRD22 deficiency contributed to IL-23 hyperproduction in the context of IMQ stimulation.

ANKRD22 deficiency-induced NIK accumulation exacerbates psoriasiform skin inflammation

To further understand how ANKRD22 deficiency caused excessive noncanonical NF-κB activation in the context of IMQ stimulation, we examined the upstream components of the noncanonical NF-κB signaling pathway. Stimulation with IMQ induced an appreciable and comparable loss of TNF receptor-associated factor 2 (TRAF2), but did not trigger the loss of TRAF3, cellular inhibitor of apoptosis protein 1 (cIAP1), or cIAP2 in WT and AKNRD22-KO BMDCs (Figure 6A). Since TRAF2 is typically involved in TNF receptor (TNFR) signaling pathways, instead of TLR pathways, we noticed a delayed kinetics of TRAF2 degradation in both WT and AKNRD22-KO BMDCs stimulated with IMQ (Figure 6B), indicating that IMQ-induced TRAF2 degradation and noncanonical NF-κB activation may be mediated by the autocrine processes of a TNFR superfamily member. One of the TNFR family members known to stimulate TRAF2 degradation is TNFRII (also called CD120b), which was abundantly and equally expressed on both WT and ANKRD22-KO BMDCs with or without TLR ligand stimulation (Figure 6C). However, a TNFRII neutralizing antibody profoundly interrupted IMQ-stimulated TRAF2 degradation, p52 and RelB nuclear translocation, and IL-23A production (Figure 6D) in both WT and ANKRD22-KO BMDCs. These results suggested that the autocrine of TNFRII was required for IMQ-stimulated noncanonical NF-κB activation and IL-23 production. Notably, NIK accumulation was dramatically increased in AKNRD22-KO BMDCs compared with that of WT BMDCs (Figure 6A). Upon incubation with MG132 (proteasome inhibitor), the level of NIK in WT BMDCs was restored to a level similar to that of ANKRD22-KO BMDCs in response to IMQ (Figure 6E), indicating that NIK stability was affected by ANKRD22 deficiency via proteolysis. In addition, ANKRD22 deficiency markedly attenuated Lys48 ubiquitination of NIK in BMDCs stimulated with IMQ (Figure 6F). Either knockdown of TRAF2 or TRAF3 (Figure S9A) or inhibition of cIAPs by their specific inhibitor Smac mimetic BV6 (Figure S9B) failed to abolish the excessive NIK accumulation in ANKRD22-KO BMDCs upon IMQ stimulation. These results strongly suggested that ANKRD22-deficiency-caused increment of NIK accumulation was independent on the cIAPs-TRAF2/3 ubiquitin ligase complex. Interestingly, we further found that ANKRD22 and NIK formed a complex in BMDCs upon IMQ stimulation, but not in resting BMDCs (Figure 6G), suggesting that ANKRD22 served as a negative regulator by targeting accumulated NIK and assisting in Lys48 ubiquitination and degradation of NIK. Moreover, we found that inhibition of NIK almost entirely abrogated the hyperproduction of IL-23 in ANKRD22-KO BMDCs (Figure 6H). More important, administration of NIK inhibitor abolished the increment in clinical and pathological symptoms of ANKRD22-KO mice with IMQ-induced psoriasis-like skin inflammation (Figures 6I–6M and S10A–S10D). In summary, our findings demonstrated that ANKRD22 deficiency led to the negative feedback loop dysfunction of NIK accumulation, resulting in excessive noncanonical NF-κB activation and IL-23 production, thereby exacerbating the IMQ-induced psoriasiform skin inflammation.

ANKRD22 is negatively associated with IL23A expression in psoriasis and accelerates the resolution of psoriasiform skin inflammation

To investigate the potential role of ANKRD22 in regulating immune dysfunction in psoriasis, we found that ANKRD22 expression was significantly decreased in lesioned dermis compared with healthy dermis, whereas IL23A was significantly increased (Figure 7A). Notably, a negative correlation was observed between the ANKRD22 expression levels and both IL23A expression and psoriasis severity, as measured by PASI scores (Figure 7B). In addition, ANKRD22 protein was colocalized with CD11c⁺ DCs in the nonlesional dermis (Figure 7C), whereas it was barely present in psoriatic lesional dermis (Figure 7C). Apart from psoriasis, publicly available datasets showed no significantly different expression of ANKRD22 in patients with atopic dermatitis or vitiligo, when compared with healthy controls (Figure S11A). To directly assess whether ANKRD22 regulates IL23A induction in human DCs, we transfected human PMDCs with small interfering (si)ANKRD22 or negative control (siNC) and then stimulated cells with IMQ or not. Knockdown of ANKRD22 led to increased IL23A expression rather than IL1B (Figure S11B) and enhanced the activation of noncanonical NF-κB, but not canonical NF-κB, as indicated by increased NIK accumulation, p52 and RelB generation, and nuclear translocation (Figure S11C). Different from IMQ stimulation, knockdown of ANKRD22 did not influence IL23A levels upon stimulation with LPS and Pam3cy (Figure S11D). These results suggested that the reduced expression of ANKRD22 in dermal DCs resulted in noncanonical NF-κB activation and IL-23 production in individuals with psoriasis, which may specifically contribute to the sustained inflammation of psoriasis. To assess the therapeutic effect of ANKRD22 on psoriasis inflammation, we then injected subcutaneously AAV carrying ANKRD22-overexpression vector into the back skin of mice during IMQ application (Figure 7D). As expected, ANKRD22 expression (EGFP) was detected in dermal DCs from AAV-ANKRD22-injected mice on day 8 postinjection and gradually increased on days 10 and 14 (Figure 7E). In line with the overexpression of ANKRD22, AAV-ANKRD22-injected mice showed a significant improvement in clinical and pathological symptoms from day 10, as evidenced by decreased PASI scores, IL-23, and epidermal hyperplasia when compared with AAV-NC-injected mice (Figures 7F and 7G). In addition, this improvement became even more pronounced on day 14 (Figures 7F, 7H, and S12). These results convincingly demonstrated that ANKRD22 accelerated the resolution of psoriasiform skin inflammation.

Discussion

The resolution of inflammation is an essential process for maintaining healthy immune function and preventing the development of autoimmune diseases.¹² Researchers are actively studying the mechanisms underlying inflammation resolution and developing new strategies to promote this process as a potential therapeutic approach for treating inflammatory diseases. Here, we discover that an AR-containing protein, namely ANKRD22, is an endogenous orchestrator mediating the resolution of psoriasiform skin inflammation. Specifically, ANKRD22 subsides the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, thereby restricting IL-23A production in dermal DCs. Of greater significance, subcutaneous administration of an ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Owing to incredible solubility, remarkable stability, and exquisite specificity for targets, AR-containing proteins are largely considered to be druggable targets.¹³^,¹⁴ Therefore, our work reveals an important role and mechanism of ANKRD22 in regulating the inflammation resolution of psoriasis and provides insight into the potential use of ANKRD22 as a therapeutic protein drug for psoriasis.

IL-17, mainly produced by Th17 and γδ T17, is the terminal pathogenic cytokine and plays a key role in the persistence of psoriasis.¹⁵^,¹⁶ IMQ-treated ANKRD22-KO mice show higher production of IL-17, as well as proportion and absolute number of dermal γδ T17 cells rather than Th17 cells. Consistent with the results of a previous study,¹⁷ dermal γδ T cells are the major cellular source of IL-17 in these mice. Therefore, the elevated production of IL-17 is mainly attributed to increased γδ T17 cells in IMQ-treated ANKRD22-KO mice. IL-17 is a granulokine, and IL-17 released from γδ T cells is shown to increase neutrophil infiltration.¹⁸ Consequently, neutrophil infiltration was significantly increased in the dermis of IMQ-treated ANKRD22-KO mice, and was well correlated with PASI scores. Unexpectedly, the differentiation rate was comparable between WT and ANKRD22-KO naive γδ T cells under γδ T17 differentiation condition in vitro. Tcrd^−/− mice displayed surprisingly mild phenotypes in response to IMQ application, whereas they developed psoriasis-like disease after being reconstituted with γδ T cells.¹⁹ Surprisingly, Tcrd^−/− mice reconstituted with ANKRD22-KO naive γδ T cells did not further strengthen their susceptibility to IMQ-induced psoriasiform skin inflammation, when compared to those reconstituted with WT naive γδ T cells. These results strongly suggest that γδ T cells were not the direct targets of ANKRD22 deficiency in mediating psoriasiform skin inflammation.

DCs are critical contributors to immune responses by bridging innate and adaptive immunity and have been implicated in the initiation of psoriasis pathogenesis by orchestrating the development of γδ T17 cells.²⁰^,²¹ Thus, we next tried to confirm whether DCs were responsible for the susceptibility of ANKRD22-KO mice to IMQ-induced psoriasiform skin inflammation by using CD11c-DTR/GFP transgenic mice.²² Indeed, the mice adoptively transferred with ANKRD22-KO BMDCs were also highly susceptible to IMQ-induced psoriasis-like disease, which recapitulated our findings in mice with a global deficiency of ANKRD22. Consistently, the differentiation of dermal γδ T17 cells was also enhanced, just as in ANKRD22 systemically deficient mice. A similar result was also obtained in a system of coculturing ANKRD22-KO BMDCs with naive γδ T cells in vitro. Previous study has demonstrated that DCs, but not macrophages, were depleted after every other day administration of DT.²⁰ Collectively, these data clearly demonstrated that ANKRD22 deficiency directly targeted DCs to facilitate IMQ-induced psoriasiform skin inflammation, with γδ T17 cells as important effector cells of DC responses.

Activation of DCs through pathogen recognition receptors promotes the production of IL-23 and IL-1β, which play a major role in the induction and/or expansion of Th17 cells and γδ T17 cells.²³ ANKRD22 deficiency led to the hyperproduction of IL-23A, but not IL-1β, IL-6, IL-12A, and TNF-α in BMDCs primed with IMQ in vitro. This contradicted to the exaltation of these cytokines in skin from IMQ-treated ANKRD22-KO mice; however, the discrepancy could be explained by the difference between internal and external environments or the feedback mechanism of psoriasis. IL-23 has been demonstrated to be a key master cytokine that promotes γδ T17 cell survival and proliferation, and targeting the IL-23p19 subunit with monoclonal antibody leads to clinical improvement in psoriasis.²⁴^,²⁵ Strikingly, the neutralization of IL-23A profoundly reduced the development of IMQ-induced psoriasis-like disease, making the clinical and pathological features comparable between WT and ANKRD22-KO mice. However, there were no apparent differences in pathological process between WT and ANKRD22-KO mice in the IL-23-induced psoriasiform model. These data demonstrated that IL-23A hyperproduction in DCs was responsible for the susceptibility of ANKRD22-KO mice to IMQ-induced psoriasiform skin inflammation. For the mechanistical insight into the role of ANKRD22 in relation to neutrophils, our results showed that ANKRD22 deficiency directly induced IL-23 hyperproduction in DCs to facilitate dysregulation of the cutaneous γδ T17 differentiation and neutrophil infiltration. Blockage of IL-17 entirely eliminated the higher neutrophil infiltration in ANKRD22-KO mice. Thus, ANKRD22 deficiency directly led to excessive and sustained IL-23 production by DCs, inducing γδ T cells to produce more IL-17 molecules, which caused higher neutrophil infiltration in the skin.

A member of the NF-κB signaling pathway, c-Rel, is involved in TLR-induced IL-23 expression in DCs.²⁶ In addition, the AP-1 family has been shown to induce IL-23 expression after TLR stimulation through activating ERK, JNK, and p38 MAPKs.²⁷ A 2018 study suggested Il23a as a major target gene of the noncanonical NF-κB pathway in DCs stimulated with TLR ligands.²⁸ Among these signaling pathways, we clarified that the noncanonical NF-κB signaling pathway was indispensable for IL-23A hyperproduction in IMQ-treated ANKRD22-KO DCs. However, noncanonical NF-κB activation is typically mediated by signals from the TNFR superfamily members,²⁹ instead of the IMQ-mediated TLR pathways. In regard to this, upregulation of TNFRII and delayed kinetics of TRAF2 degradation were observed in DCs upon IMQ stimulation, suggesting that the autocrine process of TNFRII was involved in IMQ-stimulated noncanonical NF-κB activation. Thus, it is possible that IMQ induces noncanonical NF-κB activation through the upregulation of TNFRII and induction of its ligand TNF.³⁰ However, our data did not exclude the involvement of additional TNFR members. NIK, a central signaling component of the noncanonical NF-κB signaling pathway,³¹ whose accumulation is dominated by the disintegration of the cIAPs-TRAF2/3 complex.³² Nevertheless, ANKRD22 deficiency led to a further increase in NIK accumulation in response to IMQ stimulation, regardless of the disintegration or inactivation of the cIAPs-TRAF2/3 complex. Recent studies have suggested the involvement of both cIAPs-TRAF2/3-dependent and -independent mechanisms in regulating NIK stability.³³ Thus, our studies supported the idea that ANKRD22 deficiency was responsible for cIAPs-TRAF2/3 complex-independent NIK accumulation. It is noteworthy that there was an increase in ANKRD22 protein levels after stimulation with IMQ, indicating that ANKRD22 was a negative feedback regulator of NIK accumulation. In addition, our data showed that ANKRD22 physically interacted with accumulated NIK and assisted in the ubiquitination and degradation of NIK after stimulation with IMQ. Since ANKRD22 has been reported to be a scaffold protein rather than a ubiquitinating enzyme,³⁴ further efforts are needed to investigate which E3 ubiquitin ligase is involved and how ANKRD22 modulates NIK ubiquitination. Inhibition of NIK has been found to be effective against IMQ-induced psoriasis in animal models, highlighting the potential of ANKRD22 for the treatment of psoriasis.³⁵ Indeed, subcutaneous administration of an ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Nevertheless, it is important to acknowledge the limitations of our study. Because IMQ-induced skin inflammation resembles only some features of psoriasis and resembles acute TLR7/8-induced inflammation rather than a chronic inflammatory skin disease, another mouse model (e.g., JunB^f/f c-Jun^f/f K5-Cre-ERT mice) for psoriasis would be useful to draw further conclusions on the translational aspects of the work.

IL-23/IL-17 has emerged as not only a pivotal pathogenic cytokine in autoimmunity disease but also a crucial cytokine for host protection against infections.²³ In line with this, monoclonal antibodies against IL-23 and IL-17 improve psoriatic symptoms with slightly superior short-term safety profiles, but their long-term medication may lead to psoriasis-associated opportunistic infections.³⁶^,³⁷ Previous study indicated that the reduction of IL-23 caused by NIK-KO led to mice being much more sensitive to Citrobacter rodentium infection,²⁸ suggesting an increased risk of bacterial infection by targeting NIK for psoriasis treatment. In our study, ANKRD22 specifically suppressed NIK-mediated IL-23 production upon IMQ stimulation rather than LPS stimulation. LPS ligation of TLR4 induces IL-23 production by myeloid DCs, resulting in the induction of IL-17 as part of a proinflammatory axis, which is critical for host to defense bacterial infection.³⁸^,³⁹ This indicates that application of ANKRD22, to some extent, maintains the main characteristic of DCs against bacterial infection by TLR4 activation. In addition, canonical NF-κB-mediated IL-23 production is believed to play an important role in promoting host protection from bacterial or fungal infections,⁴⁰^,⁴¹ whereas ANKRD22 rarely influenced the activation of canonical NF-κB upon IMQ stimulation. Moreover, type I interferons (IFN-α and IFN-β) derived from DCs by TLR7 signaling involvement, which was not impaired by ANKRD22, are considered to be of great relevance in the clearance of viruses.⁴²^,⁴³ Collectively, the application of ANKRD22 for the treatment of psoriasis may avoid bacterial, fungal, or viral opportunistic infections caused by monoclonal antibodies targeting IL-23/IL17.

In summary, our work reveals that ANKRD22 is crucial for the resolution of psoriasiform skin inflammation by selectively suppressing IL-23A production in DCs. Mechanistically, ANKRD22 subsides the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, in which ANKRD22 physically interacts with accumulated NIK and assists in NIK degradation by a negative feedback mechanism. Notably, subcutaneous administration of an ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our study innovatively discovers the mechanism underlying inflammation resolution of psoriasis and provides insight into the potential use of ANKRD22 as a therapeutic protein drug for psoriasis.

Materials and methods

Further information can be found in the supplemental methods.

Ethics approval

This study involves human subjects, and all of the experimental protocols, including collection of skin tissue and peripheral blood mononuclear cell from psoriasis patients and healthy volunteers, were approved by the institutional review board of The First Affiliated Hospital of Jinan University, Guangzhou, China (approval no. KY-2021-006). Subjects gave informed consent to participate in the study before taking part. All of the animal experimental procedures were approved in accordance with a code of practice established by the Jinan University Institutional Laboratory Animal Care and Use Committee (approval no. IACUC-20201125-05).

Human subjects

A total of 15 patients with psoriasis who were diagnosed with psoriasis vulgaris by pathologic examination were recruited from outpatient clinics of the First Affiliated Hospital of Jinan University. Psoriasis disease activity was assessed using the PASI score. Patient information is provided in Table S1. A total of 15 sex- and age-matched healthy controls were recruited from the medical staff at the First Affiliated Hospital of Jinan University. Psoriatic skin samples were obtained by punch biopsy under local lidocaine anesthesia. Normal skin specimens were taken from healthy adults undergoing plastic surgery. The fresh tissue samples were snap-frozen in liquid nitrogen and stored at −80°C.

Animals

ANKRD22-deficient mice on a C57BL/6J background were generated by Cyagen Biosciences. Tcrd^−/− (strain 002120) and CD11c-DTR/GFP mice (strain 004509) on a C57BL/6J background were purchased from The Jackson Laboratory and inbred at our facility. All of the mice were housed and maintained under specific pathogen-free conditions at Jinan University (Guangzhou, China).

Antibodies and reagents

The antibodies and reagents used in this study are listed in Table S2.

IMQ-induced psoriasis-like mouse model

Female or male mice (8–10 weeks of age) from the same litters and cages were treated with a daily topical dose of 62.5 mg IMQ cream (5%) on their shaved backs for 5 consecutive days.⁴⁴ In some experiments, IMQ treatment was performed for 3, 5, 7, 10, and 14 consecutive days. Control mice were treated with the same dose of vehicle cream (Vaseline). In some experiments, anti-IL-17A antibody (α-IL-17A)/anti-IL-17F(α-IL-17F) mixture (200 μg per mouse), anti-IL-23 p19-neutralization antibody (α-p19) (100 μg per mouse) versus isotype control, NIK SIM1 (50 μg per mouse) versus control buffer, or recombinant ANKRD22 (5 μg per mouse) versus control buffer were intraperitoneally or subcutaneously injected into the shaved back skin of anesthetized WT or ANKRD22-KO mice for 5 consecutive days during IMQ application. For histopathology, tissues from the euthanized animals were fixed in formalin and embedded in paraffin. Sections (5 μm thickness) were stained with H&E. For skin inflammation, an objective scoring system was developed to evaluate the severity of back skin inflammation in the IMQ-induced psoriasis-like mouse model, and this system was based on the clinical PASI score for psoriasis patients. Erythema, scaling, and thickening were scored independently on a scale of 0–4: 0, none; 1, slight; 2, moderate; 3, marked; and 4, very marked. The scoring was performed in a fully blinded fashion. The total score was obtained by adding the 3 index scores (score of 0–12). For the measurement of acanthosis, the epidermal area was outlined, and its pixel size was measured using the lasso tool in Adobe Photoshop CS4. The relative area of the epidermis was calculated using the following formula: area = pixels/(horizontal resolution × vertical resolution).

Adoptive transfer of immune cells

For the adoptive transfer of naive γδ T cells,⁴⁵ Tcrd^−/− recipient mice (7–8 weeks) were administered naive γδ T cells (2 × 10⁶) or 200 μL PBS via tail vein injection. Five days later, the reconstituted mice were subjected to the induction of psoriasis-like disease for the mouse model. For the adoptive transfer of BMDC cells, CD11c-DTR/GFP mice (7–8 weeks) were intraperitoneally injected with DT (100 ng) on day 0. The mice were administered WT or KO BMDC (2 × 10⁶) via the ophthalmic vein on day 1. The mice in the control groups received injection of sterile PBS (200 μL). The reconstituted mice were subjected to IMQ treatment from days 1 to 6. DT injection and cell transfer were performed again on days 3 and 4, respectively (Figure 3A).

Quantitative real-time (real-time qPCR)

Total RNA was isolated from DC cells or tissue using TRIzol reagent and subjected to cDNA synthesis using the PrimeScript II 1st Strand cDNA Synthesis Kit. Real-time qPCR was performed using SYBR Green qPCR Master Mix kit (Bimake) and CFX Connect Detection System (Bio-Rad). The expression of individual genes was calculated by a standard curve method and was normalized to the expression of Hprt and Gapdh. The primers used in real-time qPCR assays are shown in Table S3.

Preparation of BMDCs

BMDCs were generated by cultivating BM cells of indicated WT and KO mice in growth medium supplemented with recombinant granulocyte-monocyte-colony-stimulating factor (GM-CSF) (20 ng/mL). Fresh GM-CSF-containing medium was added on days 3 and 6, and the fully differentiated DCs were harvested on day 8 for function assay. The generated DC population was analyzed by flow cytometry based on CD11c expression and further enriched using the CD11c Positive Selection Kit. In some experiments, BMDCs were treated with IMQ (2 μg/mL), CpG (2 μg/mL), LPS (50 ng/mL), MG132 (2 μM), SN52 (5 or 10 μM), NIK SMI (0.1 or 1 μM), ERKi (0.1 or 1 μM), JNKi (1 or 10 μM), p38i (1 or 10 μM), anti-TNFRII (1 μg/mL), or Smac mimetic BV6 (2 μM).

Skin cell preparations

The dorsal skin of the mice was cut into pieces and digested at 37°C for 1 h in 10 mL DMEM medium containing collagenase IV (1 mg/mL) and DNase I (10 mg/mL) under constant stirring. After digestion, the tissue was homogenously disaggregated using the shear force with a 29G syringe. Then, 0.5% BSA and 5 mmol/L EDTA were added to quench the digestion enzymes. Next, we used a 70-mm nylon filter (BD Biosciences) to filter the isolated cells and washed them with PBS containing 2% fetal bovine serum for counting and flow cytometry staining.

Flow cytometry

For cell surface staining, cells were incubated with specific antibodies for 15 min on ice in the presence of anti-FcγR to block FcγR binding. For intracellular staining, cells were stimulated with 50 ng/mL phorbol 12-myristate 13-acetate and 1 μg/mL ionomycin in the presence of GolgiStop for 4 h. After stimulation, cells were fixed and permeabilized with BD Cytofix/Cytoperm Plus, followed by staining with fluorescent antibodies for an additional 30 min on ice in the dark. All of the samples were acquired with FACSVerse flow cytometer (BD Biosciences) and analyzed with FlowJo software (TreeStar).

In situ hybridization

In situ hybridization was performed according to the manufacturer’s instructions (Boster Technologies). The 5-μm-thick skin sections were deparaffinized and treated with H₂O₂ followed by antigen retrieval and protease treatment according to the ANKRD22 mRNA FISH Kit’s instructions. Probes to Mm-ANKRD22 were hybridized for 2 h, followed by 3 amplification steps. Nuclei were counterstained with DAPI. All of the images were collected with a Leica TCS SP2 AOBS confocal laser scanning microscope.

Immunoblot (IB) and IP

Whole-cell and subcellular extracts were prepared and subjected to IB assays essentially as described. The protein samples were separated by 8% or 12% SDS-PAGE, transferred to polyvinylidene fluoride membranes (0.22 μm, Millipore), and blocked for 2 h with 5% BSA, 0.1% Tween 20 in TBS. The membranes were then washed and incubated with primary antibodies overnight at 4°C. The goat anti-rabbit or goat anti-mouse immunoglobulin G (IgG) secondary antibodies (1:3,000 dilution) were used to incubate for 2 h. After washing, enhanced chemiluminescence (Millipore) was used to collect the chemiluminescence signals on the Bio-Rad ChemiDoc MP Gel imaging system. For IP, cells were harvested, sonicated, and immunoprecipitated with antibody specific to NIK overnight following protein A magnetic beads inoculation for 3 h. The beads were separated from solution using a magnetic separation rack, resuspended with SDS sample buffer, and heated to 95°C–100°C for 5 min. After pelleting beads using the magnetic separation rack, the supernatant was analyzed by IB.

RNA-seq analysis

Primary BMDCs from WT and ANKRD22-KO mice (8–10 weeks old) were stimulated with IMQ for 24 h. BMDCs were used for total RNA isolation with TRIzol, and subjected to RNA-seq analysis. RNA-seq was performed by Shanghai Majorbio Bio-pharm Technology using an Illumina sequencer. The raw reads were aligned to the mm10 reference genome, using HiSat2 RNA-seq alignment software. The mapping rate was 90% overall across all of the samples in the dataset. RSEM was used to quantify the gene expression counts from the HiSat2 alignment files. Differential expression analysis was performed on the count data using R package DESeq2. p values obtained from multiple binomial tests were adjusted using the false discovery rate with the Benjamini-Hochberg method. Significant genes are defined by a fold change of at least 2.0. The data were analyzed on the online platform Majorbio Cloud.

Immunofluorescence staining

Human skin samples were fixed, cryosectioned, blocked, and then stained with the following primary antibodies: anti-human or mouse ANKRD22 (Invitrogen) and phycoerythrin anti-human CD11c (BioLegend) and DAPI (Sigma). Images were acquired by Leica TCS SP5 confocal microscope system.

Construction of scAAV vector overexpressing ANKRD22

The ANKRD22 coding sequence was amplified by PCR and then cloned into an scAAV vector (serotype of AAV9, inverted terminal repeats flanking the transgene) encoding GFP under the fascin promoter. The woodchuck hepatitis virus posttranscriptional regulatory element was also included in the vector to enhance transgene expression. The scAAV vector was packaged using a triple transfection method in HEK293T cells. The cells were harvested and the virus was purified by ultracentrifugation and column chromatography. The purified virus was then quantified using qPCR to determine the viral genome (vg) titer, which was found to be 1E+13 vg/mL. For infection, female or male mice (8–10 weeks of age) from the same litters and cages were treated with a daily topical dose of 30 mg IMQ cream (5%) on the shaved back for the first 7 days and 62.5 mg IMQ cream (5%) for the next 7 days. During this period, mice were infected with scAAV virus carrying ANKRD22-overexpression or NC vector via subcutaneous injection at a dosage at 1E+11 vg at day −1, 1, and 3, respectively (Figure 7D).

Statistical analysis

The experiments for animal models were independently repeated at least twice, and other experiments were independently repeated at least three times. GraphPad Prism 8.0 was used for data analysis. Data were presented as mean ± SD. The significance of comparisons between two groups was determined by the Student’s t test and comparison of more than two groups determined by the ANOVA test. Correlation analysis was performed using Spearman’s rho test (for abnormally distributed data). p < 0.05 was considered to be statistically significant.

Data and code availability

The authors declare that all of the data are available in the main text or the supplemental information. The original datasets are also available from the corresponding author upon request. The RNA-seq data from this study are deposited in NCBI: PRJNA882212.

Acknowledgments

This work is supported by grants from the National Natural Science Foundation of China (82103722, 32030036, 31830021, 32170709, and 32100697), the Guangdong Basic and Applied Basic Research Foundation (2020A1515110052), the China Postdoctoral Science Foundation (2022M723699, China), the 111 Project (B16021), the Postdoctoral Fund of Zhuhai People’s Hospital (BSHQD2022090006 and BSHQD2023020001), and the 2022 Science and Technology Projects of Social Development in Zhuhai (2220004000064). The authors would like to thank the Institute of Molecular and Medical Virology, Jinan University for providing us with necessary experimental support by supplying laser scanning confocal microscope, ultracentrifuge and other equipment for this study.

Author contributions

Y.G. conceived and supervised the overall project. F.H. and Z.Y. consulted to and advised on the project. X.X., L.Z., and M.X. designed and performed the majority of the in vitro and in vivo studies and analyzed the data. Z.L. and G.L. provided assistance in the analysis of the transcriptome and the in vitro experiments. F.H. and H.Y. provided the skin tissue samples from healthy subjects and patients with psoriasis. Z.L., G.L., H.J., and X.W. provided technical assistance. X.X. drafted the manuscript. Z.Y. and Y.G. revised the manuscript. All of the authors have read and approved the article.

Declaration of interests

The authors declare no competing interests.

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.ymthe.2024.03.007.

Contributor Information

Zhinan Yin, Email: zhinan.yin@yale.edu.

Fang Huang, Email: huangfang67@sohu.com.

Yunfei Gao, Email: tyunfeigao@jnu.edu.cn.

Supplemental information

Docuemnt S1. Figures S1–S12 and Tables S1–S4

mmc1.pdf^{(3.5MB, pdf)}

Document S2. Article plus supplemental information

mmc2.pdf^{(12.2MB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Docuemnt S1. Figures S1–S12 and Tables S1–S4

mmc1.pdf^{(3.5MB, pdf)}

Document S2. Article plus supplemental information

mmc2.pdf^{(12.2MB, pdf)}

Data Availability Statement

[bib1] 1.Ouyang W., O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019;50:871–891. doi: 10.1016/j.immuni.2019.03.020. [DOI] [PubMed] [Google Scholar]

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PERMALINK

ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production

Xichun Xia

Leqing Zhu

Miaomiao Xu

Zhiwei Lei

Hai Yu

Guangqiang Li

Xiao Wang

Hongling Jia

Zhinan Yin

Fang Huang

Yunfei Gao

Abstract

Graphical abstract

Introduction

Results

ANKRD22 acts as an endogenous suppressor of psoriasiform skin inflammation

Figure 1.

Dysregulation of the cutaneous γδ T17 differentiation caused by ANKRD22 deletion in a cell-extrinsic manner

Figure 2.

Dendritic cell (DC)-intrinsic ANKRD22 ablation predominantly contributes to aggravated psoriasiform skin inflammation

Figure 3.

ANKRD22 deletion facilitates psoriasiform inflammation by promoting DC-derived IL-23 production

Figure 4.

Excessive noncanonical NF-κB activation caused by ANKRD22 deficiency is essential for IMQ-stimulated IL-23 induction

Figure 5.

ANKRD22 deficiency-induced NIK accumulation exacerbates psoriasiform skin inflammation

Figure 6.

ANKRD22 is negatively associated with IL23A expression in psoriasis and accelerates the resolution of psoriasiform skin inflammation

Figure 7.

Discussion

Materials and methods

Ethics approval

Human subjects

Animals

Antibodies and reagents

IMQ-induced psoriasis-like mouse model

Adoptive transfer of immune cells

Quantitative real-time (real-time qPCR)

Preparation of BMDCs

Skin cell preparations

Flow cytometry

In situ hybridization

Immunoblot (IB) and IP

RNA-seq analysis

Immunofluorescence staining

Construction of scAAV vector overexpressing ANKRD22

Statistical analysis

Data and code availability

Acknowledgments

Author contributions

Declaration of interests

Footnotes

Contributor Information

Supplemental information

References

Associated Data

Supplementary Materials

Data Availability Statement

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