The Role of Alarmins in the Pathogenesis of Rheumatoid Arthritis, Osteoarthritis, and Psoriasis.

Alarmins are immune-activating factors released after cellular injury or death. By secreting alarmins, cells can interact with immune cells and induce a variety of inflammatory responses. The broad family of alarmins involves several members, such as high-mobility group box 1, S100 proteins, interleukin-33, and heat shock proteins, among others. Studies have found that the concentrations and expression profiles of alarmins are altered in immune-mediated diseases. Furthermore, they are involved in the pathogenesis of inflammatory conditions. The aim of this narrative review is to present the current evidence on the role of alarmins in rheumatoid arthritis, osteoarthritis, and psoriasis. We discuss their potential involvement in mechanisms underlying the progression of these diseases and whether they could become therapeutic targets. Moreover, we summarize the impact of pharmacological agents used in the treatment of these diseases on the expression of alarmins.

Diagnostic and Prognostic Values of S100B versus Neuron Specific Enolase for Traumatic Brain Injury; a Systematic Review and Meta-analysis.

Introduction: Traumataic brain injury (TBI) represents a significant global health burden. This systematic review delves into the comparison of S100B and Neuron-Specific Enolase (NSE) regarding their diagnostic and prognostic accuracy in TBI within the adult population. Methods: Conducted on October 21, 2023, the search identified 24 studies encompassing 6454 adult patients. QUADAS-2 and QUAPAS tools were employed to assess the risk of bias. The analyses aimed to evaluate the diagnostic and prognostic performance of S100B and NSE based on sensitivity, specificity, and area under the curve (AUC). The outcomes were detecting intracranial injury, mortality, and unfavorable outcome. Results: Pooled data analysis tended towards favoring S100B for diagnostic and prognostic purposes. S100B exhibited a diagnostic AUC of 0.74 (95% confidence interval (CI): 0.70-0.78), sensitivity of 80% (95% CI: 63%-90%), and specificity of 59% (95% CI: 45%-72%), outperforming NSE with an AUC of 0.66 (95% CI: 0.61-0.70), sensitivity of 74% (95% CI: 53%-88%), and specificity of 46% (95% CI: 24%-69%). Notably, both biomarkers demonstrated enhanced diagnostic value when blood samples were collected within 12 hours post-injury. The analyses also revealed the excellent diagnostic ability of S100B with a sensitivity of 99% (95% CI: 4%-100%) and a specificity of 76% (95% CI: 51%-91%) in mild TBI patients (AUC = 0.89 [0.86-0.91]). In predicting mortality, S100B showed a sensitivity of 90% (95% CI: 65%-98%) and specificity of 61% (95% CI: 39%-79%), slightly surpassing NSE's performance with a sensitivity of 88% (95% CI: 76%-95%) and specificity of 56% (95% CI: 47%-65%). For predicting unfavorable outcomes, S100B exhibited a sensitivity of 83% (95% CI: 74%-90%) and specificity of 51% (95% CI: 30%-72%), while NSE had a sensitivity of 80% (95% CI: 64%-90%) and specificity of 59% (95% CI: 46%-71%). Conclusion: Although neither biomarker has shown promising diagnostic performance in detecting abnormal computed tomography (CT) findings, they have displayed acceptable outcome prediction capabilities, particularly with regard to mortality.

Calcium mediated static and dynamic allostery in S100A12: Implications for target recognition by S100 proteins.

Structure and functions of S100 proteins are regulated by two distinct calcium binding EF hand motifs. In this work, we used solution-state NMR spectroscopy to investigate the cooperativity between the two calcium binding sites and map the allosteric changes at the target binding site. To parse the contribution of the individual calcium binding events, variants of S100A12 were designed to selectively bind calcium to either the EF-I (N63A) or EF-II (E31A) loop, respectively. Detailed analysis of the backbone chemical shifts for wildtype protein and its mutants indicates that calcium binding to the canonical EF-II loop is the principal trigger for the conformational switch between 'closed' apo to the 'open' Ca2+ -bound conformation of the protein. Elimination of binding in S100-specific EF-I loop has limited impact on the calcium binding affinity of the EF-II loop and the concomitant structural rearrangement. In contrast, deletion of binding in the EF-II loop significantly attenuates calcium affinity in the EF-I loop and the structure adopts a 'closed' apo-like conformation. Analysis of experimental amide nitrogen (15 N) relaxation rates (R1 , R2 , and 15 N-{1 H} NOE) and molecular dynamics (MD) simulations demonstrate that the calcium bound state is relatively floppy with pico-nanosecond motions induced in functionally relevant domains responsible for target recognition such as the hinge domain and the C-terminal residues. Experimental relaxation studies combined with MD simulations show that while calcium binding in the EF-I loop alone does not induce significant motions in the polypeptide chain, EF-I regulates fluctuations in the polypeptide in the presence of bound calcium in the EF-II loop. These results offer novel insights into the dynamic regulation of target recognition by calcium binding and unravels the role of cooperativity between the two calcium binding events in S100A12.

Secondary Modification of S100B Influences Anti Amyloid-ß Aggregation Activity and Alzheimer's Disease Pathology.

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aß aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aß proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aß aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aß binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aß toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.

Role of innate host defense proteins in oral cancerogenesis.

It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to examine this connection because periodontitis is a highly prevalent chronic inflammatory disease and oral squamous cell carcinomas are the most common oral malignant lesions. In this review, we describe how particular molecules of the human innate host defense system may participate as molecular links between these two important chronic noncommunicable diseases (NCDs). Specific focus is directed toward antimicrobial polypeptides, such as the cathelicidin LL-37 and human defensins, as well as S100 proteins and alarmins. We report in which way these peptides and proteins are able to initiate and support oral tumorigenesis, showing direct mechanisms by binding to growth-stimulating cell surface receptors and/or indirect effects, for example, inducing tumor-promoting genes. Finally, bacterial challenges with impact on oral cancerogenesis are briefly addressed.

Generation and Application of Monoclonal Antibodies against Porcine S100A8, S100A9, and S100A12 Proteins Using Hybridoma Technology.

S100A8, S100A9, and S100A12 proteins are important members of the S100 protein family, act primarily as congenital immunomodulators, and are closely related to the occurrence of infectious diseases. There have been few reports on the functional properties of S100A8, S100A9, and S100A12 proteins in swine, but it is certain that porcine S100A8, S100A9, and S100A12 proteins are highly expressed in diseased swine. To address the current lack of reliable and timely detection tools for these three proteins, we generated monoclonal antibodies specific to the porcine S100A8, S100A9, and S100A12 proteins using hybridoma technology. The results of serum sample testing showed that the above monoclonal antibodies specifically recognize the proteins S100A8, S100A9, and S100A12 in the serum and were able to evaluate the content change of these proteins during the infection process. This provides the basis for the use of porcine S100A8, S100A9, and S100A12 in the surveillance and diagnosis of swine diseases and laid a foundation for further understanding their roles in infection, immunity, and inflammation, as well as their potential applications in preventing or treating gastrointestinal tract or inflammatory diseases in swine.

Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.

S100 proteins are small proteins that are only expressed in vertebrates. They are widely expressed in many different cell types and are involved in the regulation of calcium homeostasis, glucose metabolism, cell proliferation, apoptosis, inflammation and tumorigenesis. As members of the S100 protein subfamily of myeloid-related proteins, S100A8, S100A9 and S100A12 play a crucial role in resisting microbial infection and maintaining immune homeostasis. These proteins chelate the necessary metal nutrients of pathogens invading the host by means of 'nutritional immunity' and directly inhibit the growth of pathogens in the host. They interact with receptors on the cell surface to initiate inflammatory signal transduction, induce cytokine expression and participate in the inflammatory response and immune regulation. Furthermore, the increased content of these proteins during the pathological process makes them useful as disease markers for screening and detecting related diseases. This article summarizes the structure and function of the proteins S100A8, S100A9 and S100A12 and lays the foundation for further understanding their roles in infection, immunity and inflammation, as well as their potential applications in the prevention and treatment of infectious diseases.

Polypoid non-neural granular cell tumor of the oral cavity: case report and literature review

To report a case of non-neural granular cell tumor (NN-GCT), an uncommon neoplasm, with only six studies worldwide describing cases involving the oral cavity. Methods: A 26-year-old male patient with an erythematous, firm, polypoid nodule in the floor of the mouth that exhibited areas of ulceration and mild bleeding to the touch. A biopsy was performed to aid in the diagnosis. Results: Based on the histopathological and immunohistochemical results (vimentin +, CD68 +, S100 -), the diagnosis was compatible with S100-negative (primitive polypoid non-neural) granular cell tumor. No recurrence was observed over two years of follow-up. Conclusion: The diagnosis of NN-GCT is extremely challenging because this tumor shares histological and immunophenotypic features with many benign and malignant tumors. Although oral NN-GCT may exhibit unusual and atypical histological features, it has an indolent behavior. Thus, until more cases of oral involvement are reported, complete resection and close follow-up are recommended

Inhibition of the membrane repair protein annexin-A2 prevents tumor invasion and metastasis.

Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in invasive breast and pancreatic cancer cells. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal shear-stress damaged membrane when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and may even accelerate migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We expect that inhibiting membrane repair will be particularly effective in aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with anti-ANXA2 antibodies, which have been shown to inhibit metastasis of breast and pancreatic cancer cells, or with small molecule drugs.

S100 Proteins in the Pathogenesis of Psoriasis and Atopic Dermatitis.

The skin, the outermost layer of the human body, is exposed to various external stimuli that cause inflammatory skin reactions. These external stimulants trigger external epithelial cell damage and the release of intracellular substances. Following cellular damage or death, intracellular molecules are released that enhance tissue inflammation. As an important substance released from damaged cells, the S100 protein is a low-molecular-weight acidic protein with two calcium-binding sites and EF-hand motif domains. S100 proteins are widely present in systemic organs and interact with other proteins. Recent studies revealed the involvement of S100 in cutaneous inflammatory disorders, psoriasis, and atopic dermatitis. This review provides detailed information on the interactions among various S100 proteins in inflammatory diseases.

Comparative analysis of the physical properties of murine and human S100A7: Insight into why zinc piracy is mediated by human but not murine S100A7.

S100 proteins are a subfamily of EF-hand calcium-binding proteins found primarily in vertebrate animals. They are distinguished by binding of transition metals and functioning in both the intracellular and extracellular milieu. S100A7 functions in the protection of the skin and mucous membranes and is a biomarker in inflammatory skin disease. A recent study of Neisseria gonorrhoeae infection revealed that human but not murine S100A7 could be used to evade host nutritional immunity. To understand the molecular basis for this difference, we carried out a comparative analysis of the physical and structural properties of human and murine S100A7. The X-ray crystal structure of Ca2+-loaded mouse S100A7 (mS100A7) was determined to 1.69 Å resolution, and Ca2+-induced conformational changes were assessed by NMR. Unlike human S100A7 (hS100A7), which exhibits conformational changes in response to binding of Ca2+, no significant changes in mS100A7 were detected. Dynamic light scattering, circular dichroism, and a competition chelator assay were used to compare the Zn2+ affinity and the effects of ion binding on mS100A7 versus hS100A7. Alignment of their sequences revealed a substantial difference in the C-terminal region, which is an important mediator of protein-protein interactions, suggesting a rationale for the specificity of N. gonorrhoeae for hS100A7. These data, along with more detailed analysis of S100A7 sequence conservation across different species, support the proposal that, although hS100A7 is highly conserved in many mammals, the murine protein is a distinct ortholog. Our results highlight the potential limitations of using mouse models for studying bacterial infections in humans.

S100 proteins in head and neck squamous cell carcinoma (Review).

The most common tumor affecting the head and neck is head and neck squamous cell carcinoma (HNSCC). The characteristics of HNSCC include a rapid onset, a lack of early diagnosis, drug resistance, relapse and systemic adverse effects, leading to inadequate prevention, diagnosis and treatment. Notably, previous research suggests that there is an association between S100 proteins and HNSCC. S100A8, S100A9 and S100A14 interfere with tumor cell proliferation by blocking the cell cycle. The present review discusses this association. S100A4 enhances cancer stem cell properties, and interacts with actin and tropomyosin to promote tumor cell migration. S100A1, S100A8, S100A9, S100A10, S100A14 and S100P are involved in the initiation and progression of HNSCC via Hippo, nuclear factor κB, phosphatidylinositol kinase/protein kinase B/mammalian target of rapamycin and other signaling pathways. In addition, certain long non-coding RNAs and microRNAs are involved in regulating the expression of S100 proteins in HNSCC. Reducing the expression of certain members of the S100 protein family may enhance the chemosensitivity of HNSCC. Collectively, it is suggested that S100 proteins may function as markers and targets for the prevention, diagnosis and treatment of HNSCC.

Pathogenic role of S100 proteins in psoriasis.

Psoriasis is a chronic inflammatory skin disease. The histopathological features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis.

S100 proteins in cardiovascular diseases.

Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.

Heterogeneous effects of S100 proteins during cell interactions between immune cells and stromal cells from synovium or skin.

Cell interactions represent an important mechanism involved in the pathogenesis of chronic inflammation. The key S100 proteins A8 and A9 have been studied in several models of chronic inflammatory diseases with highly heterogeneous conclusions. In this context, the aim of this study was to determine the role of cell interactions on S100 protein production and their effect on cytokine production during cell interactions, between immune and stromal cells from synovium or skin. Peripheral blood mononuclear cells (PBMC) were cultured alone or with synoviocytes or skin fibroblasts, with or without phytohemagglutinin, exogenous A8, A9, A8/A9 proteins or anti-A8/A9 antibody. Production of IL-6, IL-1ß, IL-17, TNF, A8, A9, and A8/A9 was measured by ELISA. Cell interactions with synoviocytes had no effect on A8, A9, or A8/A9 secretion, while cell interactions with skin fibroblasts decreased A8 production. This highlights the importance of stromal cell origin. The addition of S100 proteins in co-cultures with synoviocytes did not increase the production of IL-6, IL-17, or IL-1ß, except for an increase of IL-6 secretion with A8. The presence of anti-S100A8/A9 antibody did not show obvious effects. Low concentration or absence of serum in the culture medium decreased the production of IL-17, IL-6, and IL-1ß but despite these conditions, the addition of S100 proteins did not increase cytokine secretion. In conclusion, the role of A8/A9 in cell interactions during chronic inflammation appears complex and heterogeneous, depending on multiple factors, notably the origin of stromal cells that can affect their secretion.

Immunohistochemical Analysis of S100 Proteins in Normal and Irreversibly Inflamed Human Dental Pulps.

INTRODUCTION: S100 proteins convey important roles in innate immune responses to infection and regenerative processes. However, their role in inflammatory or regenerative processes of the human dental pulp is poorly elucidated. The aim of the present study was to detect, localize, and compare the occurrence of 8 S100 proteins in normal, symptomatic, and asymptomatic irreversibly inflamed dental pulp specimens. METHODS: Human dental pulp specimens from 45 individuals were clinically assigned to 3 groups of pulpal diagnosis: normal pulp (NP, n = 17), asymptomatic irreversible pulpitis (AIP, n = 13), and symptomatic irreversible pulpitis (SIP, n = 15). The specimens were prepared and immunohistochemically stained for proteins S100A1, -A2, -A3, -A4, -A6, -A7, -A8, and -A9. Staining was classified using semiquantitative analysis and a 4-degree staining score (ie, no, decent, medium, and intense staining) at 4 different anatomic or functional regions (ie, the odontoblast layer [OL], pulpal stroma [PS], border area of calcifications [BAC], and vessel walls). The distribution of staining degrees between the 3 diagnostic groups was calculated using the Fisher exact text (P ≤ .05) at the 4 regions. RESULTS: Significant differences in staining were observed mainly in the OL and PS and at the BAC. The most significant differences were detected in the PS and when comparing NP with 1 of the 2 irreversibly inflamed pulpal tissues (AIP or SIP). The inflamed tissues were then invariably stained more intensely than their normal counterparts at this location (S100A1, -A2, -A3, -A4, -A8, and -A9). In the OL, NP tissue was significantly stronger stained for S100A1, -A6, -A8, and -A9 compared with SIP and for S100A9 when compared with AIP. Differences between AIP and SIP in direct comparison were rare and were found only for 1 protein (S100A2) at the BAC. Also, at the vessel walls, only 1 statistical difference in staining was observed (SIP was stronger stained than NP for protein S100A3). CONCLUSIONS: The occurrence of proteins S100A1, -A2, -A3, -A4, -A6, -A8, and -A9 is significantly altered in irreversibly inflamed compared with normal dental pulp tissue at different anatomic localizations. Some members of S100 proteins obviously participate in focal calcification processes and pulp stone formation of the dental pulp.

Toward an understanding of the conformational plasticity of S100A8 and S100A9 Ca2+-binding proteins.

S100A8 and S100A9 are small, human, Ca2+-binding proteins with multiple intracellular and extracellular functions in signaling, regulation, and defense. The two proteins are not detected as monomers but form various noncovalent homo- or hetero-oligomers related to specific activities in human physiology. Because of their significant roles in numerous medical conditions, there has been intense research on the conformational properties of various S100A8 and S100A9 proteoforms as essential targets of drug discovery. NMR or crystal structures are currently available only for mutated or truncated protein complexes, mainly with bound metal ions, that may well reflect the proteins' properties outside cells but not in other biological contexts in which they perform. Here, we used structural mass spectrometry methods combined with molecular dynamics simulations to compare the conformations of wildtype full-length S100A8 and S100A9 subunits in biologically relevant homo- and heterodimers and in higher oligomers formed in the presence of calcium or zinc ions. We provide, first, rationales for their functional response to changing environmental conditions, by elucidating differences between proteoforms in flexible protein regions that may provide the plasticity of the binding sites for the multiple targets, and second, the key factors contributing to the variable stability of the oligomers. The described methods and a systematic view of the conformational properties of S100A8 and S100A9 complexes provide a basis for further research to characterize and modulate their functions for basic science and therapies.

Tau liquid-liquid phase separation is modulated by the Ca2+ -switched chaperone activity of the S100B protein.

Aggregation of the microtubule-associated protein tau is implicated in several neurodegenerative tauopathies including Alzheimer's disease (AD). Recent studies evidenced tau liquid-liquid phase separation (LLPS) into droplets as an early event in tau pathogenesis with the potential to enhance aggregation. Tauopathies like AD are accompanied by sustained neuroinflammation and the release of alarmins at early stages of inflammatory responses encompass protective functions. The Ca2+ -binding S100B protein is an alarmin augmented in AD that was recently implicated as a proteostasis regulator acting as a chaperone-type protein, inhibiting aggregation and toxicity through interactions of amyloidogenic clients with a regulatory surface exposed upon Ca2+ -binding. Here we expand the regulatory functions of S100B over protein condensation phenomena by reporting its Ca2+ -dependent activity as a modulator of tau LLPS induced by crowding agents (PEG) and metal ions (Zn2+ ). We observe that apo S100B has a negligible effect on PEG-induced tau demixing but that Ca2+ -bound S100B prevents demixing, resulting in a shift of the phase diagram boundary to higher crowding concentrations. Also, while incubation with apo S100B does not compromise tau LLPS, addition of Ca2+ results in a sharp decrease in turbidity, indicating that interactions with S100B-Ca2+ promote transition of tau to the mixed phase. Further, electrophoretic analysis and FLIM-FRET studies revealed that S100B incorporates into tau liquid droplets, suggesting an important stabilizing and chaperoning role contributing to minimize toxic tau aggregates. Resorting to Alexa488-labeled tau we observed that S100B-Ca2+ reduces the formation of tau fluorescent droplets, without compromising liquid-like behavior and droplet fusion events. The Zn2+ -binding properties of S100B also contribute to regulate Zn2+ -promoted tau LLPS as droplets are decreased by Zn2+ buffering by S100B, in addition to the Ca2+ -triggered interactions with tau. Altogether this work uncovers the versatility of S100B as a proteostasis regulator acting on protein condensation phenomena of relevance across the neurodegeneration continuum.

Novel Functional Peptide for Next-Generation Vital Pulp Therapy.

Although vital pulp therapy should be performed by promoting the wound-healing capacity of dental pulp, existing pulp-capping materials were not developed with a focus on the pulpal repair process. In previous investigations of wound healing in dental pulp, we found that organic dentin matrix components (DMCs) were degraded by matrix metalloproteinase-20, and DMC degradation products containing protein S100A7 (S100A7) and protein S100A8 (S100A8) promoted the pulpal wound-healing process. However, the direct use of recombinant proteins as pulp-capping materials may cause clinical problems or lead to high medical costs. Thus, we hypothesized that functional peptides derived from recombinant proteins could solve the problems associated with direct use of such proteins. In this study, we identified functional peptides derived from the protein S100 family and investigated their effects on dental pulp tissue. We first performed amino acid sequence alignments of protein S100 family members from several mammalian sources, then identified candidate peptides. Next, we used a peptide array method that involved human dental pulp stem cells (hDPSCs) to evaluate the mineralization-inducing ability of each peptide. Our results supported the selection of 4 candidate functional peptides derived from proteins S100A8 and S100A9. Direct pulp-capping experiments in a rat model demonstrated that 1 S100A8-derived peptide induced greater tertiary dentin formation compared with the other peptides. To investigate the mechanism underlying this induction effect, we performed liquid chromatography-tandem mass spectrometry analysis using hDPSCs and the S100A8-derived peptide; the results suggested that this peptide promotes tertiary dentin formation by inhibiting inflammatory responses. In addition, this peptide was located in a hairpin region on the surface of S100A8 and could function by direct interaction with other molecules. In summary, this study demonstrated that a S100A8-derived functional peptide promoted wound healing in dental pulp; our findings provide insights for the development of next-generation biological vital pulp therapies.