Psoriasis is a multifaceted immune-inflammatory disorder, with genetic inheritance being one of its primary pathogenic factors[1]. In the present study, the polymorphisms of NLRP12 gene and its association with susceptibility to in psoriasis were investigated. We found a significant increase in the mutation frequency of NLRP12 rs12460528 co-dominant model in psoriasis, particularly in the dominant model. The NLRP12 rs12460528, as a synonymous mutation, does not alter the amino acid sequence, but it can affect the binding of transcription factors and alters the secondary structure and stability of mRNA, ultimately leading to changes in protein conformation[15, 16]. It is known that synonymous codons encode same amino acids, but the translation rate of different synonymous mutant codons is different, which will lead to the change of translation optimality[17, 18]. Consequently, this mutation may impact the occurrence of psoriasis. As all known, NLRP12 is a member of the NLR family, which has been proven in the pathogenesis inflammatory diseases, including infections and autoimmune disorders[19–24]. Previous studies only found an association between mutations in this gene locus and familial cold-induced autoinflammatory syndrome, a rare autosomal dominant disorder that may develop from deletion or alteration of the NLRP12 gene[25]. This study presents the first evidence of a potential correlation between this specific site and psoriasis. We found that the genetic polymorphism was consistent with the common mutation base type (G/A) and gene frequency at this site, thereby confirming the accuracy of the NLRP12 mutation. In light of the increased frequency of the NLRP12 rs12460528 mutation, it is plausible to suggest that this genetic variant may contribute to an augmented susceptibility towards psoriasis.
Actually, the NLRP12 gene has been frequently mentioned in inflammatory diseases and has been identified as a risk gene for Post Traumatic Stress Disorder (PTSD) alongside TNF-α[26], which is predicted to be an upstream regulator of cardiovascular disease. The NLRP12 rs34436714 has been reported to be associated with depression, while the NLRP12 rs34971363 and rs6509825 are associated with an increased coronary artery calcification score[26]. Additionally, a study conducted on Dai ethnic Chinese population found an association between hypertension and the NLRP12 rs34436714[27]. The NLRP12 gene and autoinflammatory syndrome are frequently reported, often resulting in harmful and pathogenic effects[28–32]. Ghosh reported a case of a deleterious sequence change in the NLRP12 gene identified in India, resulting in NLRP12-related autoinflammation[33]. The aforementioned evidence highlights the significant association between alterations in the NLRP12 gene and inflammatory disorders. Therefore, it is reasonable to postulate that NLRP12 may also exert a similarly pivotal role in the pathogenesis of psoriasis.
To further investigate the function of NLRP12 in the psoriasis, we conducted quantitative real-time PCR to determine the expression levels of NLRP12 mRNA in both blood leukocytes and psoriatic tissues. We were surprised to discover a significant increase in the expression level of NLRP12 mRNA, which was positively correlated with IL-17A. These findings suggest that NLRP12 may participate in the same pathway as IL-17A in the pathogenesis of psoriasis and play a pro-inflammatory role, contradicting previous founding in psoriasis comorbidities such as obesity, inflammatory bowel disease (IBD), and type 2 diabetes mellitus[6, 11, 34, 35]. Actually, the role of NLRP12 remains controversial, as it has been shown to function as both a negative regulator of inflammation and as an inflammasome. NLRP12 acts as a negative regulator, regulating both the typical and non-typical NF-κB and MAPK pathways, as well as activating T cell NF-κB and ERK to reduce inflammation[36]. Recent research has revealed that NLRP12 additionally regulates dendritic cell and neutrophil migration to modulate contact hypersensitivity[37] .Notably, previous studies have reported the involvement of the NLRP12-IL-17A-CXCL1 axis in regulating neutrophil recruitment to combat extracellular pathogens[38]. On the other hand, NLRP12 produces immune effects in the form of inflammasomes in infections such as Yersinia pestis and Plasmodium chabaudi[23, 39]. Due to the intricate and conflicting functions of NLRP12 within the human organism, further investigation is warranted to elucidate the precise pathway by which NLRP12 contributes to inflammation in psoriasis.
Likewise, the results of Western Blot and immunohistochemical assays indicated an upregulation of NLRP12 protein expression in psoriasis. IHC revealed a higher expression of NLRP12 in psoriatic epidermis compared to the control group, accompanied by significant neutrophil infiltration in the corneum of common psoriasis vulgaris. To our knowledge, NLRP12 is predominantly expressed in myeloid cells, such as macrophages, dendritic cells, monocytes and neutrophils[10]. Based on our findings, we have found that NLRP12, an intracellular inflammatory factor, exerts a crucial influence on the activation of neutrophils and macrophages, thereby contributing significantly to the pathogenesis of psoriasis-related inflammation. However, considering the significant role of neutrophils in psoriasis pathogenesis, further investigation is required to ascertain whether it is possible to regulate the development of psoriasis through immune cells such as neutrophils. Meanwhile, we hypothesized that the NLRP12 is one of the key points in the regulation of these immune cells in the skin spinous layer. Further investigation is necessary to confirm the precise localization of NLRP12 within this layer of skin in order to gain a better understanding of its exact location and function within psoriatic lesions.