Introduction

Sjögren’s disease (SD) is a chronic autoimmune disease primarily characterized by lymphocytic infiltration of exocrine glands, leading to a hallmark triad of symptoms: xerostomia (dry mouth), keratoconjunctivitis sicca (dry eyes), and systemic manifestations that may involve the joints, skin, and internal organs.1 The exact etiology of SD remains elusive, but it is understood to involve a complex interplay of genetic predisposition, environmental factors, and dysregulated immune responses, resulting in the loss of tolerance to self-antigens.2

Recent advancements in molecular biology have uncovered the critical role of microRNAs (miRNAs), which are small, non-coding RNA molecules approximately 21–25 nucleotides in length.3 MiRNAs function as key post-transcriptional regulators of gene expression by binding to complementary sequences on target messenger RNAs (mRNAs), leading to mRNA degradation or repression of translation.4 This regulatory mechanism allows miRNAs to orchestrate numerous biological processes, including cell proliferation, differentiation, apoptosis, and immune response modulation.5,6

The groundbreaking discoveries made by Victor Ambros and Gary Ruvkun in the field of miRNA biology have provided invaluable insights into the functional roles of these molecules across various biological systems.7 Their work has demonstrated how miRNAs can act as critical regulators in numerous diseases, including cancer, cardiovascular disorders, and autoimmune conditions.

In SD, an increasing body of evidence suggests that miRNAs play pivotal roles in the disease’s pathogenesis.8 For instance, specific miRNAs have been implicated in the modulation of immune cell functions, including the activation of autoreactive T and B cells, the regulation of pro-inflammatory cytokines, and the maintenance of epithelial integrity within exocrine glands.9,10 Dysregulation of miRNAs has been associated with altered immune responses, contributing to the chronic inflammation and tissue damage observed in SD. Moreover, the expression profiles of miRNAs in the serum and salivary glands of SD patients have been shown to differ significantly from those of healthy individuals, suggesting their potential as biomarkers for disease diagnosis and progression.11 Furthermore, targeting specific miRNAs offers a promising therapeutic avenue, as modulation of miRNA expression could restore normal immune function and ameliorate glandular damage.

This review aims to provide a comprehensive overview of the role of miRNAs in the pathophysiology of SD. By synthesizing current knowledge on the interactions between miRNAs and immune system dynamics, we hope to illuminate the potential of miRNAs as biomarkers and therapeutic targets, ultimately enhancing our understanding and management of this multifaceted autoimmune disorder.

Biogenesis of MicroRNAs and Their Role in Sjögren’s Disease

MiRNAs are a class of important non-coding RNA molecules, typically consisting of 21 to 25 nucleotides, that play a crucial role in gene regulation.12 The biogenesis of miRNAs begins with the transcription of primary miRNA transcripts (pri-miRNAs), which are synthesized by RNA polymerase II and form a hairpin structure known as precursor miRNA (pre-miRNA).13 In the nucleus, the enzyme Drosha, in association with the cofactor DGCR8, processes pri-miRNA into pre-miRNA.14 Subsequently, pre-miRNAs are exported to the cytoplasm via Exportin-5, where they are further cleaved by the enzyme Dicer into mature miRNAs.15 These mature miRNAs are then incorporated into the RNA-induced silencing complex (RISC), where they guide the complex to target mRNAs based on sequence complementarity, leading to either mRNA degradation or the inhibition of translation, thus regulating gene expression16Figure 1.

Figure 1 Mechanisms of miRNA-mediated regulation of gene expression. The process of miRNA maturation begins in the nucleus and is first transcribed by RNA polymerase II to generate longer pri-miRNAs. Such initial transcripts usually contain one or more stem-loop structures. Subsequently, Drosha/Pasha in the nucleus recognizes and cleaves pri-miRNAs to process them into pre-miRNAs. After further processing and transport, pre-miRNAs are transported into the cytoplasm. In the cytoplasm, Dicer enzyme will further cleave the pre-miRNA, removing its stem-loop structure and producing a mature miRNA duplex of approximately 21 to 25 base pairs, which is then loaded into miRNP. Binding of miRNP to target mRNA sequences that can lead to mRNA degradation (A) or/and inhibition of mRNA translation into protein (B) are two typical mechanisms of miRNA action. The binding of some miRNAs to certain targets has been shown to increase translation (C) rather than inhibit it. In addition, several miRNA species have been shown to bind to gene promoter sequences in the nucleus, acting as transcriptional activators (D) or silencers (E).

In SD, dysregulation of miRNAs has been closely linked to the pathogenesis and progression of the disease.17 Specific miRNAs play pivotal roles in the activation of immune cells, where they influence immune responses by modulating the expression of cytokines.18

Epithelial Cells

Epithelial cells play a crucial role in the pathogenesis of SD. These cells, particularly in exocrine glands like salivary and lacrimal glands, contribute significantly to glandular dysfunction, which is a hallmark of SD. Dysregulation of miRNAs in epithelial cells can exacerbate inflammation, impair cell-cell communication, and disrupt epithelial integrity, leading to the chronic inflammation and glandular damage observed in SD. Several miRNAs have been implicated in epithelial dysfunction in SD. For example, miR-155 is upregulated in epithelial cells in the context of SD and has been shown to modulate inflammation by regulating the expression of cytokines like TNF-α and IL-6. Additionally, miR-146a, which is widely studied for its role in immune regulation, also affects epithelial cells. It targets genes such as TRAF6 and IRAK1, which are involved in inflammatory signaling pathways like NF-κB, contributing to epithelial dysfunction and promoting inflammation. Furthermore, miR-21 is another key regulator in epithelial cells that has been associated with fibrosis and tissue remodeling, both of which are common in SD. miR-21 acts by regulating PTEN and other pathways involved in cell survival and apoptosis, which can lead to tissue damage when dysregulated.

These miRNAs not only contribute to epithelial dysfunction but also present potential as biomarkers for disease activity, reflecting the extent of epithelial injury and inflammation in SD. Dysregulated miRNAs in epithelial cells thus serve as promising targets for therapeutic intervention, with the potential to restore epithelial homeostasis and limit the inflammatory response that drives disease progression in SD.

T Cells

T cells are critical mediators of the adaptive immune response and are implicated in the pathogenesis of SD. In SD, the balance between different T cell subsets is disrupted. CD4+ T helper (Th) cells, particularly Th17 cells, have been shown to be prominent in the salivary glands of SD patients.19 MiR-155 is crucial in promoting Th17 differentiation, enhancing the production of pro-inflammatory cytokines such as IL-17, which contributes to tissue inflammation and damage.20 Additionally, miR-146a helps regulate T cell activation and limits excessive inflammatory responses, suggesting a dual role of miRNAs in maintaining immune homeostasis and promoting autoimmunity.21 Specifically, miR-146a targets several key genes involved in immune responses, including TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are critical for the NF-κB signaling pathway. By downregulating these genes, miR-146a modulates the activation of pro-inflammatory cytokines and contributes to the resolution of inflammation. This regulatory mechanism underscores the complex role of miR-146a in controlling immune responses, preventing excessive inflammation, and potentially limiting the development of autoimmune conditions like SD.

B Cells

B cells are central to the autoimmune process in SD due to their role in producing autoantibodies against self-antigens, such as Ro/SSA and La/SSB.22 The dysregulation of miRNAs like miR-21 and the miR-17-92 cluster enhances B cell survival and proliferation.23,24 miR-21 promotes the activation of B cells and inhibits their apoptosis, allowing autoreactive B cells to persist.25 Additionally, the expression of these miRNAs leads to increased secretion of autoantibodies, perpetuating the autoimmune response and contributing to the symptoms of SD.

Dendritic Cells

Dendritic cells (DCs) function as antigen-presenting cells that activate T cells and initiate immune responses.26,27 In SD, DCs exhibit abnormal activation, which can be influenced by miRNAs such as miR-125b and miR-155.28,29 MiR-155 enhances the production of pro-inflammatory cytokines (such as IL-6 and TNF-α) and promotes the activation of naive T cells into autoreactive T cell populations.30 Dysregulated DC function can lead to enhanced presentation of self-antigens, driving the autoimmune process in SD.

Macrophages

Macrophages play a crucial role in the inflammatory milieu of SD. They can polarize into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, significantly influencing the immune landscape.31 In SD, the imbalance between these phenotypes is often observed. MiR-155 has been implicated in promoting the M1 phenotype, leading to increased production of inflammatory cytokines.32 Conversely, miR-146a can favor the M2 phenotype, which is associated with tissue repair.33 However, the persistent activation of M1 macrophages contributes to tissue damage and chronic inflammation in SD.

Natural Killer Cells

Natural killer (NK) cells are part of the innate immune system and contribute to the immune surveillance of autoreactive cells.34 In SD, NK cells can exert both protective and pathogenic roles. They produce cytokines such as IFN-γ that can enhance the inflammatory response. MiRNAs like miR-15a and miR-16 are involved in regulating NK cell activation and proliferation.35–37 Dysregulated NK cell activity may lead to increased tissue damage and exacerbate autoimmune processes in SD.

Regulatory T Cells

Tregs are essential for maintaining immune tolerance and preventing autoimmune responses regulatory T cells (Tregs).38 In SD, the function of Tregs is often impaired, leading to a breakdown of tolerance to self-antigens. MiR-146a is critical for Treg function, and its dysregulation can impair the suppressive capacity of Tregs.39,40 As a result, the lack of effective Treg-mediated control allows for the expansion of autoreactive T and B cells, contributing to the pathogenesis of SD.

Neutrophils

Neutrophils are key players in the innate immune response and are involved in the initial stages of inflammation in SD.41 They release various pro-inflammatory mediators and can contribute to tissue damage. MiRNAs regulate neutrophil activation, survival, and chemotaxis. For instance, specific miRNAs can modulate the production of chemokines that attract other immune cells to the site of inflammation.42 In SD, the persistent activation of neutrophils can contribute to the chronic inflammatory state characteristic of the disease.

Mast Cells

Mast cells are implicated in various inflammatory and allergic responses.43 They release histamine and a range of cytokines and chemokines that can exacerbate inflammation in SD.44 The regulation of mast cells by miRNAs can influence their activation and the subsequent inflammatory response.45,46 Dysregulated mast cell activity may contribute to the exacerbation of symptoms in SD, particularly in the context of glandular dysfunction. Table 1 summarized the role of miRNA in those immune cell regulation and Sjogren syndrome.

Table 1 Role of MicroRNAs in Immune Cell Function and Their Implications in Sjogren Syndrome

Clinical Implications and Therapeutic Potential of MicroRNAs in Sjögren’s Disease

The distinctive expression profiles of miRNAs in patients with SD offer promising avenues for clinical applications. Given the critical roles that miRNAs play in the disease’s pathophysiology, they hold the potential to serve as non-invasive biomarkers for several key aspects of SD.

Diagnostic and Prognostic Biomarkers

Recent studies have indicated that specific miRNA signatures can be detected in the saliva and serum of SD patients, distinguishing them from healthy individuals.47 For example, elevated levels of certain miRNAs, such as miR-21 and miR-155, correlate with disease activity and severity.8 These miRNAs can reflect the inflammatory state and immune dysregulation characteristic of SD.48 Consequently, identifying these unique miRNA profiles may facilitate earlier diagnosis, allowing for timely interventions. Additionally, monitoring changes in miRNA levels over time can provide valuable insights into disease progression, making them potential biomarkers for tracking disease activity and evaluating therapeutic responses.48

Personalized Treatment Strategies

The identification of miRNA signatures in SD patients also paves the way for personalized treatment strategies. By understanding the specific miRNAs associated with an individual’s disease profile, clinicians may tailor therapeutic approaches to target these molecules. For instance, patients exhibiting high levels of pro-inflammatory miRNAs could benefit from treatments aimed at inhibiting these specific miRNAs, thus potentially alleviating inflammation and tissue damage.49 Conversely, patients with downregulated miRNAs that play protective roles may benefit from therapies designed to restore their levels, thereby enhancing immune regulation and promoting glandular function.50

Therapeutic Interventions Targeting miRNAs

The therapeutic potential of miRNAs in SD is an emerging area of research. Several innovative approaches are being explored, including the use of miRNA mimics and inhibitors. miRNA mimics are designed to replicate the function of downregulated miRNAs, restoring their expression and, consequently, their regulatory roles in the immune response. For example, delivering mimics of miR-146a could help enhance the regulatory pathways that control immune responses and mitigate excessive inflammation in SD.51 On the other hand, miRNA inhibitors, also known as antagomirs or anti-miRs, are utilized to suppress the activity of overexpressed miRNAs that contribute to the pathogenesis of SD. For instance, inhibiting miR-155, which is linked to the activation of autoreactive T and B cells, could reduce inflammatory cytokine production and diminish the autoimmune response.52

Preclinical studies have shown promising results with these approaches, demonstrating that modulating miRNA levels can positively impact immune function and inflammation in models of autoimmune disease. These findings lay the groundwork for future clinical trials aimed at assessing the safety and efficacy of miRNA-based therapies in SD.

Discussion

The investigation of miRNAs in SD sheds light on their crucial roles in immune regulation and disease progression.53 Recent studies have shown that specific miRNAs can serve as indicators of the disease, helping to distinguish SD patients from healthy individuals. For example, elevated levels of miR-21 and miR-155 have been detected in the saliva and serum of those with SD, correlating with the severity of inflammation and immune dysfunction.54 This suggests that miRNAs could play a significant role in diagnosing SD non-invasively, which would allow for earlier intervention and more tailored treatment approaches. By monitoring changes in miRNA levels, clinicians might gain valuable insights into disease activity, leading to better management strategies for patients.

Moreover, the therapeutic potential of targeting miRNAs in SD is becoming increasingly apparent. Techniques such as miRNA mimics and inhibitors present innovative ways to restore normal immune function. For instance, increasing the levels of miR-146a could help dampen the inflammation that characterizes SD by enhancing immune regulation. On the other hand, inhibiting miR-155 may reduce the activation of autoreactive T and B cells, ultimately lessening the autoimmune response. Preliminary studies in animal models have shown that these interventions can positively impact immune function and tissue integrity, setting the stage for future clinical trials.55

Additionally, integrating miRNA research with emerging technologies could further our understanding of SD. Techniques like single-cell RNA sequencing and CRISPR gene editing offer exciting opportunities to explore the specific roles of miRNAs in different immune cell types. This could help reveal the complex regulatory networks at play in SD and identify additional therapeutic targets.56 As we continue to learn more about the functions of miRNAs and their interactions with the immune system, we open up new avenues for developing targeted therapies that could significantly change how we approach the treatment of SD.18

In summary, the growing interest in miRNAs within the context of SD highlights their importance not only in understanding the disease but also in improving diagnostic and therapeutic strategies. By leveraging the unique properties of miRNAs, we can potentially enhance our approaches to managing this complex autoimmune condition, ultimately benefiting patients through more effective care and treatment options.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Traditional Chinese Medicine Research Program of Heilongjiang Province (No. ZHY2023-166 and 2019MS08).

Disclosure

The authors declare no competing interests in this work.

References

1. Andre F, Bockle BC. Sjogren’s syndrome. J Dtsch Dermatol Ges. 2022;20:980–1002. doi:10.1111/ddg.14823

2. Stefanski AL, Tomiak C, Pleyer U, et al. The diagnosis and treatment of Sjogren’s syndrome. Dtsch Arztebl Int. 2017;114:354–361. doi:10.3238/arztebl.2017.0354

3. Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–5465. doi:10.1002/jcp.27486

4. Pozniak T, Shcharbin D, Bryszewska M. Circulating microRNAs in medicine. Int J Mol Sci. 2022;23:3996. doi:10.3390/ijms23073996

5. Su D, Swearson S, Krongbaramee T, et al. Exploring microRNAs in craniofacial regenerative medicine. Biochem Soc Trans. 2023;51:841–854. doi:10.1042/BST20221448

6. Shao Y, Fu J, Zhan T, et al. Inhibition of CD4 + T cells by fanchinoline via miR506-3p/NFATc1 in Sjogren’s syndrome. Inflammopharmacology. 2023;31:2431–2443. doi:10.1007/s10787-023-01279-w

7. Burki T. 2024 Nobel Prize awarded for work on microRNAs. Lancet. 2024;404:1507–1508. doi:10.1016/S0140-6736(24)02303-1

8. Zehrfeld N, Abelmann M, Benz S, et al. miRNAs as potential biomarkers for subclinical atherosclerosis in Sjogren’s disease. RMD Open. 2024;10:e004434. doi:10.1136/rmdopen-2024-004434

9. Cai Y, Zhang Y, Wang S, Changyong E. MiR-23b-3p alleviates Sjogren’s syndrome by targeting SOX6 and inhibiting the NF-kappaB signaling. Mol Immunol. 2024;172:68–75. doi:10.1016/j.molimm.2024.06.002

10. He F, Yu J, Ma S, et al. MiR-34a promotes mitochondrial pathway of apoptosis in human salivary gland epithelial cells by activating NF-kappaB signaling. Arch Biochem Biophys. 2024;758:110063. doi:10.1016/j.abb.2024.110063

11. Chu WX, Ding C, Du Z-H, et al. SHED-exos promote saliva secretion by suppressing p-ERK1/2-mediated apoptosis in glandular cells. Oral Dis. 2024;30:3066–3080. doi:10.1111/odi.14776

12. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597–610. doi:10.1038/nrg2843

13. Rani V, Sengar RS. Biogenesis and mechanisms of microRNA-mediated gene regulation. Biotechnol Bioeng. 2022;119:685–692. doi:10.1002/bit.28029

14. Guo WT, Wang Y. Dgcr8 knockout approaches to understand microRNA functions in vitro and in vivo. Cell mol Life Sci. 2019;76:1697–1711. doi:10.1007/s00018-019-03020-9

15. Wu K, He J, Pu W, Peng Y. The role of exportin-5 in MicroRNA biogenesis and cancer. Genomics Proteomics Bioinf. 2018;16:120–126. doi:10.1016/j.gpb.2017.09.004

16. Bhattacharjee S, Roche B, Martienssen RA. RNA-induced initiation of transcriptional silencing (RITS) complex structure and function. RNA Biol. 2019;16:1133–1146. doi:10.1080/15476286.2019.1621624

17. Kadkhoda S, Ghafouri-Fard S. Function of miRNA-145-5p in the pathogenesis of human disorders. Pathol Res Pract. 2022;231:153780. doi:10.1016/j.prp.2022.153780

18. Cha S, Mona M, Lee KE, Kim DH, Han K. MicroRNAs in Autoimmune Sjogren’s Syndrome. Genomics Inform. 2018;16:e19. doi:10.5808/GI.2018.16.4.e19

19. Xiao F, Rui K, Han M, et al. Artesunate suppresses Th17 response via inhibiting IRF4-mediated glycolysis and ameliorates Sjogren’s syndrome. Signal Transduct Target Ther. 2022;7:274. doi:10.1038/s41392-022-01103-x

20. Kim HJ, Park SO, Byeon HW, et al. T cell-intrinsic miR-155 is required for Th2 and Th17-biased responses in acute and chronic airway inflammation by targeting several different transcription factors. Immunology. 2022;166:357–379. doi:10.1111/imm.13477

21. Li B, Wang X, Choi IY, et al. miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity. J Clin Invest. 2017;127:3702–3716. doi:10.1172/JCI94012

22. Du W, Han M, Zhu X, et al. The multiple roles of B cells in the pathogenesis of Sjogren’s syndrome. Front Immunol. 2021;12:684999. doi:10.3389/fimmu.2021.684999

23. Miao BP, Zhang R-S, Li M, et al. Nasopharyngeal cancer-derived microRNA-21 promotes immune suppressive B cells. Cell Mol Immunol. 2015;12:750–756. doi:10.1038/cmi.2014.129

24. Kuo G, Wu CY, Yang HY. MiR-17-92 cluster and immunity. J Formos Med Assoc. 2019;118:2–6. doi:10.1016/j.jfma.2018.04.013

25. Thapa DR, Bhatia K, Bream JH, et al. B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas. AIDS. 2012;26:1177–1180. doi:10.1097/QAD.0b013e3283543e0e

26. Zhou J, Zhang X, Yu Q. Plasmacytoid dendritic cells promote the pathogenesis of Sjogren’s syndrome. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166302. doi:10.1016/j.bbadis.2021.166302

27. Hillen MR, Ververs FA, Kruize AA, Van Roon JA. Dendritic cells, T-cells and epithelial cells: a crucial interplay in immunopathology of primary Sjogren’s syndrome. Expert Rev Clin Immunol. 2014;10:521–531. doi:10.1586/1744666X.2014.878650

28. Pereira CA, Freire JA, Rassi RH, Pereira LF. [Are corticosteroids necessary in the treatment of acute non-severe asthma?]. Rev Paul Med. 1988;106:28–34.

29. Dueck A, Eichner A, Sixt M, Meister G. A miR-155-dependent microRNA hierarchy in dendritic cell maturation and macrophage activation. FEBS Lett. 2014;588:632–640. doi:10.1016/j.febslet.2014.01.009

30. Etna MP, Sinigaglia A, Grassi A, et al. Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells. PLoS Pathog. 2018;14:e1006790. doi:10.1371/journal.ppat.1006790

31. Zhou D, McNamara NA. Macrophages: important players in primary Sjogren’s syndrome? Expert Rev Clin Immunol. 2014;10:513–520. doi:10.1586/1744666X.2014.900441

32. Ge X, Tang P, Rong Y, et al. Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-kappaB signaling pathway in vascular endothelial cells after traumatic spinal cord injury. Redox Biol. 2021;41:101932. doi:10.1016/j.redox.2021.101932

33. Ding J, Zhang Y, Cai X, et al. Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion. Theranostics. 2021;11:5813–5830. doi:10.7150/thno.58731

34. Zhou X, Li Q, Li Y, et al. Diminished natural killer T-like cells correlates with aggravated primary Sjogren’s syndrome. Clin Rheumatol. 2022;41:1163–1168. doi:10.1007/s10067-021-06011-z

35. Pathania AS, Prathipati P, Olwenyi OA, et al. miR-15a and miR-15b modulate natural killer and CD8(+)T-cell activation and anti-tumor immune response by targeting PD-L1 in neuroblastoma. Mol Ther Oncolytics. 2022;25:308–329. doi:10.1016/j.omto.2022.03.010

36. Kitadate A, Ikeda S, Teshima K, et al. MicroRNA-16 mediates the regulation of a senescence-apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas. Oncogene. 2016;35:3692–3704. doi:10.1038/onc.2015.435

37. Di Pace AL, Pelosi A, Fiore PF, et al. MicroRNA analysis of Natural Killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against pancreatic cancer cells. Oncoimmunology. 2023;12:2221081. doi:10.1080/2162402X.2023.2221081

38. Ho P, Cahir-McFarland E, Fontenot JD, et al. Harnessing regulatory T cells to establish immune tolerance. Sci Transl Med. 2024;16:eadm8859. doi:10.1126/scitranslmed.adm8859

39. Lu J, Wang W, Li P, et al. MiR-146a regulates regulatory T cells to suppress heart transplant rejection in mice. Cell Death Discov. 2021;7:165. doi:10.1038/s41420-021-00534-9

40. Zhang Y, Yang Y, Guo J, et al. miR-146a enhances regulatory T-cell differentiation and function in allergic rhinitis by targeting STAT5b. Allergy. 2022;77:550–558. doi:10.1111/all.15163

41. Peng Y, Wu X, Zhang S, et al. The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sjogren’s syndrome. Arthritis Res Ther. 2022;24:170. doi:10.1186/s13075-022-02860-4

42. Jiao Y, Zhang T, Zhang C, et al. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care. 2021;25:356. doi:10.1186/s13054-021-03775-3

43. Kaieda S, Fujimoto K, Todoroki K, et al. Mast cells can produce transforming growth factor beta 1 and promote tissue fibrosis during the development of Sjogren’s syndrome-related sialadenitis. Mod Rheumatol. 2022;32:761–769. doi:10.1093/mr/roab051

44. Shemesh R, Laufer-Geva S, Gorzalczany Y, et al. The interaction of mast cells with membranes from lung cancer cells induces the release of extracellular vesicles with a unique miRNA signature. Sci Rep. 2023;13:21544. doi:10.1038/s41598-023-48435-4

45. Zhang Y, Bai H, Zhang W, et al. miR-212/132 attenuates OVA-induced airway inflammation by inhibiting mast cells activation through MRGPRX2 and ASAP1. Exp Cell Res. 2023;433:113828. doi:10.1016/j.yexcr.2023.113828

46. Montagner S, Orlandi EM, Merante S, Monticelli S. The role of miRNAs in mast cells and other innate immune cells. Immunol Rev. 2013;253:12–24. doi:10.1111/imr.12042

47. Kakan SS, Janga SR, Cooperman B, et al. Small RNA deep sequencing identifies a unique miRNA signature released in serum exosomes in a mouse model of Sjogren’s syndrome. Front Immunol. 2020;11:1475. doi:10.3389/fimmu.2020.01475

48. Jin F, Hu H, Xu M, et al. Serum microRNA profiles serve as novel biomarkers for autoimmune diseases. Front Immunol. 2018;9:2381. doi:10.3389/fimmu.2018.02381

49. Hatam S. MicroRNAs improve cancer treatment outcomes through personalized medicine. microRNA. 2023;12:92–98. doi:10.2174/2211536612666230202113415

50. Ya J, Bayraktutan U. Vascular ageing: mechanisms, risk factors, and treatment strategies. Int J Mol Sci. 2023;24:11538. doi:10.3390/ijms241411538

51. Traber GM, Yu AM. RNAi-based therapeutics and novel RNA bioengineering technologies. J Pharmacol Exp Ther. 2023;384:133–154. doi:10.1124/jpet.122.001234

52. Thompson AAR, Lawrie A. Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol Med. 2017;23:31–45. doi:10.1016/j.molmed.2016.11.005

53. Reale M, D’Angelo C, Costantini E, et al. MicroRNA in Sjogren’s Syndrome: their Potential Roles in Pathogenesis and Diagnosis. J Immunol Res. 2018;2018:7510174. doi:10.1155/2018/7510174

54. Baldini C, Ferro F, Elefante E, Bombardieri S. Biomarkers for Sjogren’s syndrome. Biomarker Med. 2018;12:275–286. doi:10.2217/bmm-2017-0297

55. Lopes AP, van Roon JAG, Blokland SLM, et al. MicroRNA-130a contributes to type-2 classical DC-activation in Sjogren’s syndrome by targeting mitogen- and stress-activated protein kinase-1. Front Immunol. 2019;10:1335. doi:10.3389/fimmu.2019.01335

56. Konsta OD, Thabet Y, Le Dantec C, et al. The contribution of epigenetics in Sjogren’s Syndrome. Front Genet. 2014;5:71. doi:10.3389/fgene.2014.00071