Psoriasis is an immune-mediated skin disease. Although great advances have been made in search for psoriasis pathogenesis and treatment, therapeutic approaches are still limited for the cure. In this work, we took advantage of big data analysis, in combination with CIBERSORT algorithms, to explore novel insights into the innate immune status in psoriasis and identify prognostic biomarkers.
We found considerable differences of innate immune cell composition between psoriatic skin and control group (non-lesional or normal skin). Results revealed that γδ T cells, resting NK cells, M0 macrophages, M1 macrophages, activated dendritic cells and neutrophils were significantly increased in psoriatic skin, while resting mast cells and active NK cells were significantly decreased. Moreover, the proportion of M0 macrophages was associated with disease severity and treatment efficacy. Macrophages are considered to originate from peripheral monocytes, which enter tissue and differentiate under stimulation of the local environment. Unactivated M0 macrophages could polarize into M1 or M2 macrophages under different cytokines. M1 macrophages are implicated in activating inflammatory response, while M2 macrophages are involved in resolution of inflammation. Previous study showed that when peripheral monocytes derived from psoriasis patients were induced in vitro, the ratio of M1/M2 macrophage polarization was higher, compared with healthy control. It indicates that monocytes in psoriasis might undergo a reprogramming process-trained immunity, acquiring the preference to M1 polarization. Derived from monocytes, M0 macrophages in psoriatic plaque might also be reprogrammed in the same way. In addition, IL-23 promoted expression of IL-17A, IL-17F, IFN-γ and IL-22 in M0 macrophages, and IL-23-treated M0 macrophages significantly enhanced psoriasis-like dermatitis in mice model. Moreover, M0 macrophages were susceptible to this IL-23-driven M(IL-23) differentiation, while surprisingly M1 and M2 macrophages were highly resistant to polarization into M(IL-23) macrophages. We unexpectedly found that IL-17F expression was positively related to the proportion of M0 macrophages in lesional skin. IL-23 is highly expressed in psoriatic skin. Under IL-23 stimulation, M0 macrophages might play an unexpected and important effect in psoriasis pathogenesis. .
γδ T cells were source of IL-17 and increased in psoriatic skin. Murine models lacking γδ T revealed inhibited psoriasiform symptoms and inflammation. In psoriasis vulgaris patient blood, NK cells were reported to have reduced cytotoxicity and production of pro-inflammatory cytokines TNF-α and IFN-γ. However, another study showed that NK cells isolated from psoriatic skin secreted more IFN-γ. Researches about NK cells involved in psoriasis are insufficient, and the role in pathogenesis is not clear. Activated DCs played a pivotal role in psoriasis pathogenesis. They not only initiated the inflammation, but also sustained it. Activated mast cells were elevated in psoriatic plaque and produced IL-17, IL-22. In our analysis, the fraction of activated mast cells was rare. It is possible that CIBERSORT enumerates mainly IgE-activated mast cells, for which gene expression signature employed for deconvolution was acquired from mast cells induced by IgE. While activation of mast cells by IL-1 was an important process in skin inflammation and implicated in psoriasis pathogenesis. Recent studies revealed that neutrophils in psoriatic plaque generated abundant neutrophil extracellular trap, degranulation and the respiratory burst with ROS production, contributing to the pathogenesis of psoriasis. Collectively, different innate immune cells infiltrated in skin could play various roles in psoriasis development and progression. The specific function of some types remain to be elucidated.
Further analysis found that RORC and S100A12 were associated with psoriasis severity. The nuclear receptor retinoic acid receptor-related orphan receptor gamma (murine form “RORγ” or human form “RORC”) was a key transcription factor for the production of IL-17 and involved in inflammatory response of psoriasis. Compared with severe psoriasis, mild psoriasis was characterized by higher IL-17A expression in psoriatic lesion, which is consistent with the alteration of RORC in our study. Among S100 proteins, serum S100A12 level revealed the closest association with psoriasis disease activity-PASI. We also found this positive correlation in psoriatic plaque. Ubiquitination, a type of post-translational modification, is viewed as an important regulator in psoriasis pathogenesis, through modulation of key transcription factors or signaling molecules. RORγt, a splice variant of RORγ, could be modulated by both ubiquitination and deubiquitylation. In this work, GSEA analysis indicated that low RORC expression or high S100A12 expression was associated with ubiquitination-proteasome system. This suggests that expression of RORC and S100A12 might be regulated by ubiquitination, which is related with the modulation of psoriasis severity.
Ustekinumab and brodalumab are monoclonal antibodies applied for psoriasis treatment. Ustekinumab can inhibit IL-23 pathway by binding to the common p40 subunit of IL-12/IL-23, while brodalumab targets IL-17 receptor A and blocks IL-17 pathway. This study revealed that multiple genes were related with therapeutic efficacy. After activation, AIM2 assembles inflammasome, driving IL-1β secretion and contributing to psoriasis. Ngoungoure reported that M1 polarized macrophages expressed higher AIM2, compared with resting THP-1 macrophages. In this work, AIM2 expression was positively correlated with M1 macrophage fraction in psoriatic plaque, indicating that AIM2 might regulate psoriasis progression through modulating M1 macrophages. However, its relationship with treatment response was inconsistent in brodalumab and ustekinumab. AIM2 might play a different effect on IL-17 and IL-23 pathway and it needs to be further explored.
CLEC4C is a plasmacytoid dendritic cells (pDCs)-specific receptor. Cross-linking CLEC4C with monoclonal antibodies could lead to receptor internalization, rapid Ca2+ influx, and inhibition of IFN-I response in pDCs. We found CLEC4C expression was positively correlated with therapeutic efficacy with brodalumab, which might be a result of CLEC4C engagement induced by monoclonal antibody brodalumab. CLEC4C could not only predict brodalumab treatment response, but also be exploit as a target for selecting therapeutic monoclonal antibodies. IL-19 could amplify IL-17A effects on keratinocytes in psoriasis. We found IL-19 expression was negative correlated with anti-IL-17RA therapy.
IL-17F is a subtype of IL-17. Previous study reported that IL-17F polymorphism rs763780 was associated with better efficacy of anti-TNF therapy. In this study, low IL-17F expression was also linked to better response to anti-IL-23 treatment. PPARGC1A interacts with PPARγ and is a transcriptional coactivator. During acute colitis, PPARGC1A activation in intestinal CD11b-CD103+DCs promoted production of retinoic acid, which subsequently acted on CD11b+CD103+DCs to suppress IL-23 secretion. There is no report about PPARGC1A in psoriasis. Based on previous work and our finding of negative correlation between PPARGC1A and activated DCs, we presume that PPARGC1A might inhibit DC production of IL-23. Therapy by blocking IL-23 might not act well in moderate-to-severe psoriasis with high PPARGC1A expression, for suppressed IL-23 may not be therapy target in these patients. In sum, these results indicate that these genes may have important clinical implications in psoriasis and deserve deeper investigation.
However, this study has limitation. The number of samples for clinical association analysis was relatively small. Large sample clinical studies need to be conducted to validate our results.