High mobility group box 1 (HMGB1) is a highly conserved non-histone nucleoprotein with a size of approximately 30 kDa ^[1][72]. It comprises two cognate DNA-binding domains and a negatively charged C-terminal domain ^[2][73]. HMGB1 is present in all higher eukaryotic cells and assists in DNA replication, transcription, and repair by binding to chromatin in the nucleus ^[3][74]. Importantly, it also functions as a DAMP in infection, inflammation, and immune processes, primarily by stimulating TLR2, TLR4, and RAGE receptors. In recent years, increasing evidence suggests that HMGB1 is closely linked to psoriasis. For instance, researchers have detected a significant elevation of serum HMGB1 levels in psoriasis patients compared to healthy individuals, with levels being closely related to disease severity ^[4][75]. In addition, the expression of HMGB1 in the lesion sites of psoriasis patients was also significantly increased compared with healthy people ^[5][76].

HMGB1 is involved in psoriasis progression through several mechanisms. A study by Zhen Wang et al. revealed that HMGB1 promotes the expression of psoriasis-associated cytokines and antimicrobial peptides by activating autophagy in keratinocytes. HMGB1 also amplifies the IL-23/IL-17 immune cycle by activating dermal γδ T cells to produce IL-17A ^[6][77]. Furthermore, HMGB1 upregulates the expression of TLR2, TLR4, and RAGE in the skin lesion area of psoriasis and activates the inflammasome and NF-κB pathway in keratinocytes to promote IL-18 secretion, which would aggravate the condition of IMQ model psoriasis mice ^[7][78]. In addition, Lisa Strohbuecker et al. conducted a comprehensive study on the relationship between HMGB1 and immune cells, revealing that HMGB1 expression was markedly elevated in the psoriatic skin lesions, and its receptor RAGE expression was also significantly increased on CD8⁺ cells and CD4⁺ Treg cells within the skin lesion area, which was strongly associated with the disease progression in psoriasis ^[8][79]. Collectively, HMGB1 plays a crucial role in both downstream keratinocytes and upstream immune cells.

The role of HMGB1 in psoriasis has been extensively studied, and its potential as a therapeutic target has been demonstrated in various preclinical studies. HMGB1 knockdown or inhibition using antibodies or small molecules have shown significant improvements in psoriasis symptoms in animal models. For example, Hmgb1-KD mice and mice treated with HMGB1 antibodies exhibited improved disease outcomes after IMQ-induced psoriasis modeling ^[6][77]. Additionally, treatment with the HMGB1 inhibitor glycyrrhizin alleviated the condition of IMQ psoriasis mice ^[7][78]. The mechanism of action of HMGB1 blockade involves the inhibition of Th17 cell responses, the reduction in γδ T cells, and the regulation of inflammatory cytokine expression, such as IL-6, TNF-α, IFN-γ, and IL-17, leading to the suppression of clinical and histological evolution of IMQ-treated skin ^[7][9][78,80]. Interestingly, the mechanism of action of HMGB1 has also been implicated in existing psoriasis drugs, such as methotrexate (MTX), which inhibits the interaction between HMGB1/RAGE by binding to the RAGE binding region of HMGB1 ^[10][81]. Overall, HMGB1 is an important DAMP in the pathogenesis of psoriasis and a promising diagnostic and therapeutic target.

The S100 protein family consists of 25 members that share a molecular weight of about 10–12 kDa and maintain an amino acid sequence similarity of 25–65% ^[11][12][82,83]. Most S100 proteins are Ca²⁺ signaling proteins that contain a conserved calcium-binding motif called EF-hand. Upon binding to Ca²⁺, S100 proteins interact with other proteins to regulate a range of cellular functions, including cell migration, proliferation, apoptosis, and maintenance of Ca²⁺ homeostasis ^[13][84]. When released outside the cell as DAMPs, S100 proteins play a pro-inflammatory role by binding to receptors such as TLRs and RAGE ^[11][82]. In psoriasis, S100A7, S100A8, S100A9, S100A12, and S100A5, defined as “antimicrobial peptides”, are the main S100 family members involved. They are released by keratinocytes and activate innate immunity ^[14][85]. Among them, S100A7 is overexpressed in the damaged skin of psoriasis patients but tends to decrease in serum with increasing disease severity ^[15][86]. In contrast, both S100A8 and S100A9 are significantly increased in the serum and damaged skin of psoriasis patients ^[16][87].

The role of S100 family proteins in regulating psoriasis is still controversial. Hu Lei et al. demonstrated that human S100A7 aggravates psoriasis severity by inducing the expression of interleukin 1α in mature epidermal keratinocytes through the RAGE-p38 MAPK-calpain 1 pathway ^[17][62]. In a model of psoriasis induced by IMQ, Joan Defrêne et al. found that S100A8 inhibits the proliferation of keratinocytes and regulates their differentiation ^[18][88]. However, some scholars suggest that S100 family proteins are mainly secreted by keratinocytes and act on immune cells. Carolin Christmann et al. found that the expression of S100A8/S100A9 did not significantly affect the maturation and inflammatory response patterns of keratinocytes in primary S100a9^−/− keratinocytes, indicating that keratinocytes are not the target cells for the pro-inflammatory effect of S100A8/S100A9 ^[19][89].

The potential of S100s as targets for psoriasis diagnosis and treatment has been suggested. Henry J. Grantham et al. proposed that S100A8/9 in serum can serve as a biological indicator of atherosclerosis caused by psoriasis ^[20][90]. Helia B. Schonthaler et al. identified S100A9 as a chromatin component that regulates C3 expression in mouse and human cells by binding to a region upstream of the C3 initiation site. Knocking out S100A9 in a psoriasis mouse model strongly attenuated psoriasiform skin disease and inflammation, with reduced C3 volume and mild immune infiltration ^[21][91]. However, the study by Joan Defrêne et al. showed that S100A8 and S100A9 knockout mice had more severe symptoms after IMQ-induced psoriasis modeling, with increased IL-17 responses in the dermis and lymph nodes, indicating the anti-inflammatory properties of S100A8 and S100A9 ^[18][88]. Overall, while the S100 family is involved in regulating multiple immune pathways in psoriasis, its main role requires further investigation.

Heat shock proteins (HSPs) are a ubiquitous class of proteins that are synthesized in response to conditions such as heat shock, heavy metals, infection, or an abnormal physiological state. They have intracellular and extracellular functions. Intracellular HSPs are involved in protein folding, recognizing and binding nascent polypeptide chains and partially folded intermediates of proteins to prevent their aggregation and misfolding ^[22][92]. In contrast, extracellular HSPs function as DAMPs. Among them, HSP60, HSP70, and HSP90 are mainly involved in psoriasis and act through receptors such as TLR2, TLR4, and CD91 ^[23][24][93,94]. Studies have shown that the average IRID (immunoreactivity intensity distribution index) score of HSP60 expression in the basal, suprabasal, and superficial epidermal layers of psoriatic skin is higher than that of healthy skin ^[25][95]. HSP70 is also expressed in the skin of psoriasis sufferers but primarily in the basal layer ^[26][96]. HSP90 expression increases throughout the year with the frequency of psoriasis exacerbations, and psoriasis-related hyperlipidemia or diabetes also upregulates HSP90 expression ^[27][97]. These studies have shown that the expression levels of HSP family proteins are closely related to the severity of psoriasis.

Recent studies have shed light on the mechanisms underlying the involvement of HSP family proteins in the regulation of psoriasis. For example, O. Boyman et al. reported that dendritic antigen-presenting cells expressing the HSP receptor CD91 accumulate during the occurrence of psoriasis lesions, accompanied by activation of NF-κB and increased production of TNF. This suggests that HSP family proteins may affect the migration of dendritic cells through CD91 ^[28][98]. Furthermore, Jonathan L. et al. demonstrated that HSP can induce the maturation of blood-derived DCs, accompanied by increased IL-12 production and enhanced antigen presentation function ^[29][99]. The anti-inflammatory pain drug luteolin can regulate the ratio of immune cells by inhibiting the expression of HSP90 and exosome secretion and relieving the lesions and symptoms of psoriasis ^[30][100]. In addition, some drugs treat psoriasis by targeting the MAPK pathway and inhibiting the expression of HSP90 and HSP60 in keratinocytes ^[31][101]. HSP90 inhibitors have been shown to significantly improve psoriasis symptoms in a xenograft mouse model ^[32][102]. Specifically, Rikke S. Hansen et al. demonstrated that HSP90 inhibitors can reduce the expression of pro-inflammatory cytokines IL-23, IL-6, and TNF caused by activation of TLR3 in keratinocytes, leading to a reduction in the inflammatory response ^[33][103].

Other DAMPs, such as cytosolic DNA, ATP, self-RNA, the LL37 complex, and IL-33, are also implicated in psoriasis. For instance, the release of cytosolic DNA as DAMP induces the synergistic activation of STING in immune cells and keratinocytes, amplifying the inflammatory response in psoriasis ^[34][104]. ATP released from keratinocytes triggers the Koebner phenomenon in psoriasis ^[35][105]. The self-RNA and LL37 complex can activate DC to generate inflammatory cytokines and aggravate psoriasis ^[36][106]. IL-33 can worsen the condition of IMQ psoriasis model mice, reduce CD4 + T and CD8 + T cells in the spleen of psoriatic mice, inhibit autophagy in the skin, and promote STAT3 tyrosine phosphorylation ^[37][107]. In summary, despite the critical roles of various DAMPs in regulating inflammation in psoriasis (Table 1), further studies are required to explore their specific functions and mechanisms.