Specialized pro‐resolving mediators: wiring the circuitry of effector immune and tissue homeostasis

Inflammation when uncontrolled is associated with prevalent disorders such as arthritis and periodontal disease, diabetes and cardiovascular diseases. Hence mechanisms to dampen the inflammatory response and promote resolution are of immense interest. Recent evidence has prompted a paradigm shift whereby the resolution of acute inflammation is now considered a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)‐derived autacoids. Among these are specialized pro‐resolving mediators (SPMs) that comprise lipoxins, resolvins, protectins and maresins. SPMs are endogenous stereoselective, potent mediators that temper both the magnitude and duration of inflammatory responses. Moreover, an appreciation of these endogenous mediators and pathways that control timely resolution opens a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. The focus of this review is to depict recent advances on the biosynthesis and actions of these novel pro‐resolving and protective lipid mediators. Collectively, these findings indicate that defective mechanisms and pathways in resolution may underlie the unchecked inflammatory phenotype(s) that characterize some prevalent human diseases.     

Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases

The periodontal diseases are infectious diseases caused by predominantly Gram-negative bacteria. However, as our understanding of the pathogenesis of the periodontal diseases grows, it is becoming clear that most of the tissue damage that characterizes periodontal disease is caused by the host response to infection, not by the infectious agent directly. Investigation into the mechanism of action of host-mediated tissue injury has revealed that the neutrophil plays an important role in destruction of host tissues. In this paper, we review the biochemical pathways and molecular mediators that are responsible for regulation of the inflammatory response in diseases such as periodontitis, with a focus on lipid mediators of inflammation. Pro-inflammatory mediators, such as prostaglandins and leukotrienes, are balanced by counter-regulatory signals provided by a class of molecules called lipoxins. The role of lipoxins in the control and resolution of inflammation is discussed, as is the possibility of the development of new therapeutic strategies for the control and prevention of neutrophil-mediated tissue injury in inflammatory diseases like periodontitis.     

特异性促炎症消退介质在牙周炎中的研究进展

炎症消退机制是机体维持稳态的重要途径,是一个涉及大量免疫细胞和介质的程序化的主动过程。特异性促炎症消退介质（SPM）包括消退素、保护素和噬消素（maresins）,是Ω-3多不饱和脂肪酸衍生的一类内源性脂质介质,在促炎症消退、宿主防御、器官保护和组织再生方面都可发挥积极作用。牙周炎是以菌斑生物膜为始动因素的牙周组织炎症性、破坏性疾病。不完善的促炎或促炎症消退机制,以及两者之间的失衡状态是牙周炎病理进展的重要因素。SPM结合组织特异性受体能够改善牙周组织炎症状态,保护牙槽骨,促进组织再生,调节免疫细胞抵抗致病菌。本文就SPM对牙周炎的作用,应用前景及面临的挑战作一综述。     

Effect of salivary agglutination on oral streptococcal clearance by human polymorphonuclear neutrophil granulocytes

Salivary agglutination is an important host defense mechanism to aggregate oral commensal bacteria as well as invading pathogens. Saliva flow and subsequent swallowing more easily clear aggregated bacteria compared with single cells. Phagocytic clearance of bacteria through polymorphonuclear neutrophil granulocytes also seems to increase to a certain extent with the size of bacterial aggregates. To determine a connection between salivary agglutination and the host innate immune response by phagocytosis, an in vitro agglutination assay was developed reproducing the average size of salivary bacterial aggregates. Using the oral commensal Streptococcus gordonii as a model organism, the effect of salivary agglutination on phagocytic clearance through polymorphonuclear neutrophil granulocytes was investigated. Here we describe how salivary aggregates of S. gordonii are readily cleared through phagocytosis, whereas single bacterial cells showed a significant delay in being phagocytosed and killed. Furthermore, before phagocytosis the polymorphonuclear neutrophil granulocytes were able to induce a specific de‐aggregation, which was dependent on serine protease activity. The data presented suggest that salivary agglutination of bacterial cells leads to an ideal size for recognition by polymorphonuclear neutrophil granulocytes. As a first line of defense, these phagocytic cells are able to recognize the aggregates and de‐aggregate them via serine proteases to a more manageable size for efficient phagocytosis and subsequent killing in the phagolysosome. This observed mechanism not only prevents the rapid spreading of oral bacterial cells while entering the bloodstream but would also avoid degranulation of involved polymorphonuclear neutrophil granulocytes, so preventing collateral damage to nearby tissue.     

Differential capacity for complement receptor‐mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte

The complement system plays a central role in immunity and inflammation, although certain pathogens can exploit complement to undermine protective immunity. In this context, the periodontal keystone pathogen Porphyromonas gingivalis was previously shown by our group to evade killing by neutrophils or macrophages through exploitation of complement C5a receptor 1 (C5aR1) and complement receptor 3 (CR3). Here, we examined whether P. gingivalis uses complement receptors to also subvert killing by dendritic cells. In line with earlier independent studies, intracellular viable P. gingivalis bacteria could be recovered from mouse bone‐marrow‐derived dendritic cells (BMDC) or human monocyte‐derived dendritic cells (MDDC) exposed to the pathogen. However, in the presence of C5a, the intracellular survival of P. gingivalis was significantly decreased in a C5aR1‐dependent way. Further work using wild‐type and receptor‐knockout BMDC showed that, in the presence of C3a, the C3a receptor (C3aR) similarly enhanced the intracellular killing of P. gingivalis. In contrast, C5aR2, an alternative receptor for C5a (G protein‐coupled receptor 77), was associated with increased intracellular P. gingivalis viable counts, consistent with the notion that C5aR2 functions as a negative regulator of C5aR1 activity. Moreover, P. gingivalis failed to use CR3 as a phagocytic receptor in BMDC, in contrast to our earlier findings in macrophages where CR3‐mediated uptake promotes P. gingivalis survival. Collectively, these data show that complement receptors mediate cell‐type‐specific effects on how innate leukocytes handle P. gingivalis, which appears to exploit complement to preferentially evade those cells (neutrophils and macrophages) that are most often encountered in its predominant niche, the periodontal pocket.     

Liver X receptors contribute to periodontal pathogen‐elicited inflammation and oral bone loss

Periodontal diseases are chronic oral inflammatory diseases that are polymicrobial in nature. The presence of specific bacteria in subgingival plaque such as Porphyromonas gingivalis is associated with microbial dysbiosis and the modulation of host immune response. Bacterially elicited innate immune activation and inflammation are key elements implicated in the destruction of soft and hard tissues supporting the teeth. Liver X receptors (LXRs) are nuclear hormone receptors with important function in lipid homeostasis, inflammation, and host response to infection; however, their contribution to chronic inflammatory diseases such as periodontal disease is not understood. The aim of this study was to define the contribution of LXRs in the development of immune response to P. gingivalis and to assess the roles that LXRs play in infection‐elicited oral bone loss. Employing macrophages, we observed that P. gingivalis challenge led to reduced LXRα and LXRβ gene expression compared with that observed with unchallenged wild‐type cells. Myeloid differentiation primary response gene 88 (MyD88)‐independent, Toll/interleukin‐1 receptor‐domain‐containing adapter‐inducing interferon‐β (TRIF)‐dependent signaling affected P. gingivalis‐mediated reduction in LXRα expression, whereas neither pathway influenced the P. gingivalis effect on LXRβ expression. Employing LXR agonist and mice deficient in LXRs, we observed functional effects of LXRs in the development of a P. gingivalis‐elicited cytokine response at the level of the macrophage, and participation of LXRs in P. gingivalis‐elicited oral bone loss. These findings identify novel importance for LXRs in the pathogenesis of P. gingivalis infection‐elicited inflammation and oral bone loss.     

Macrophage tolerance response to Aggregatibacter actinomycetemcomitans lipopolysaccharide induces differential regulation of tumor necrosis factor-alpha, interleukin-1 beta and matrix metalloproteinase 9 secretion

Background and Objective: The lipopolysaccharide of Aggregatibacter actinomycetemcomitans, a potent stimulator of the immune system, induces the secretion of inflammatory mediators that modulate periodontal tissue destruction. In this study, we investigated the tolerance response of human macrophages to stimulation with A. actinomycetemcomitans lipopolysaccharide. Material and Methods: U937 monocytes were differentiated into adherent macrophage‐like cells by treatment with phorbol myristic acid. Macrophage‐like cells were then pretreated for 24 h with either 0.01 or 0.1 μg/mL LPS A. actinomycetemcomitans. Culture medium supernatants were removed and cells were restimulated with LPS at 1 μg/mL. Cell‐free supernatants were collected after 24 h of stimulation and analyzed by ELISA for TNF‐α, IL‐1β, IL‐6, IL‐8, PGE₂ and MMP‐9. Results: Phorbol myristic acid‐differentiated U937 macrophages treated with low doses of lipopolysaccharide developed tolerance to subsequent lipopolysaccharide treatments, resulting in significantly reduced secretion of tumor necrosis factor‐α. However, this tolerance response was associated with increased secretion of interleukin‐1β and matrix metalloproteinase 9, whereas the secretion of interleukin‐6, interleukin‐8 and prostaglandin E₂ was unaffected. Phosphatidylinositol‐3′‐kinase inhibitors added during the tolerance‐induction period markedly attenuated the increase in interleukin‐1β secretion but had no effect on tumor necrosis factor‐α. Conclusion: This study showed that A. actinomycetemcomitans lipopolysaccharide can induce a tolerance response in macrophages that alters the secretion of two important inflammatory mediators as well as of the tissue‐degrading enzyme matrix metalloproteinase‐9. This phenomenon may play a role in modulating the host inflammatory response and the progression of periodontitis.     

Oral candidosis in relation to oral immunity

Symptomatic oral infection with Candida albicans is characterized by invasion of the oral epithelium by virulent hyphae that cause tissue damage releasing the inflammatory mediators that initiate and sustain local inflammation. Candida albicans triggers pattern‐recognition receptors of keratinocytes, macrophages, monocytes and dendritic cells, stimulating the production of IL‐1β, IL‐6 and IL‐23. These cytokines induce the differentiation of Th17 cells and the generation of IL‐17‐ and/or IL‐22‐mediated antifungal protective immuno‐inflammatory responses in infected mucosa. Some immune cells including NKT cells, γδ T cells and lymphoid cells that are innate to the oral mucosa have the capacity to produce large quantities of IL‐17 in response to C. albicans, sufficient to mediate effective protective immunity against C. albicans. On the other hand, molecular structures of commensal C. albicans blastoconidia, although detected by pattern‐recognition receptors, are avirulent, do not invade the oral epithelium, do not elicit inflammatory responses in a healthy host, but induce regulatory immune responses that maintain tissue tolerance to the commensal fungi. The type, specificity and sensitivity of the protective immune response towards C. albicans is determined by the outcome of the integrated interactions between the intracellular signalling pathways of specific combinations of activated pattern‐recognition receptors (TLR2, TLR4, Dectin‐1 and Dectin‐2). IL‐17‐mediated protective immune response is essential for oral mucosal immunity to C. albicans infection.     

消退素在炎症消退中的研究进展及其在牙髓炎症调控中的应用

炎症消退是一个主动的程序化过程。由内源性脂质调控介质控制炎症反应,促进炎症及时消退对于防止炎症反应过度至关重要。消退素是最近发现的一类具有较强抗炎作用的内源性脂质调控介质。研究表明消退素可以限制中性粒细胞的过度活化和募集、促进凋亡和坏死细胞的清除、并且对结构细胞可起到保护作用,从而加速炎症的消退,恢复组织稳态。局部应用消退素,炎症细胞对牙髓和根尖周组织的浸润也明显减少。     

Enhanced monocyte migration and pro‐inflammatory cytokine production by Porphyromonas gingivalis infection

Pollreisz A, Huang Y, Roth GA, Cheng B, Kebschull M, Papapanou PN, Schmidt AM, Lalla E. Enhanced monocyte migration and pro‐inflammatory cytokine production by Porphyromonas gingivalis infection. J Periodont Res 2009; doi: 10.1111/j.1600‐0765.2009.01225.x. © 2009 The Authors. Journal compilation © 2009 Blackwell Munksgaard Background and Objective: Porphyromonas gingivalis, a major periodontal pathogen, has been reported to be involved in atherogenesis. In order to further understand this pathogen’s link with systemic inflammation and vascular disease, we investigated its influence on murine monocytes and macrophages from three different sources. Material and Methods: Concanavalin A‐elicited peritoneal macrophages, peripheral blood monocyte‐derived macrophages and WEHI 274.1 monocytes were infected with either P. gingivalis 381 or its non‐invasive fimbriae‐deficient mutant, DPG3. Results: Infection with P. gingivalis 381 markedly induced monocyte migration and significantly enhanced production of the pro‐inflammatory cytokines, tumor necrosis factor‐α and interleukin‐6. Consistent with a role for this pathogen’s major fimbriae and/or its invasive capacity, infection with DPG3 had a minimal effect on both monocyte attraction and pro‐inflammatory cytokine production. Conclusion: Since monocyte recruitment and activation are important steps in the development of vascular inflammation and atherosclerosis, these results suggest that P. gingivalis infection may be involved in these processes.     

Binding of Actinobacillus actinomycetemcomitans lipopolysaccharides to Peptostreptococcus micros stimulates tumor necrosis factor α production by macrophage‐like cells

Peptostreptococcus micros is a gram‐positive bacterium that has been associated with periodontitis and endodontic infections. In this study, we hypothesized that P. micros binds the immunomodulating component lipopolysaccharide derived from gram‐negative bacteria to increase its capacity to stimulate cytokine production by host cells. The ability of P. micros to bind Actinobacillus actinomycetemcomitans lipopolysaccharide was demonstrated by an enzyme‐linked immunosorbent assay and by immunoelectron microscopy. Pretreatment of P. micros cells with A. actinomycetemcomitans lipopolysaccharide was associated with a 49‐fold increase in tumor necrosis factor alpha production by human monocytic cells U937 differentiated into adherent macrophages, compared to the stimulation with untreated P. micros. This effect was suppressed by incorporating polymyxin B, a lipid A‐binding substance, during treatment of macrophage‐like cells with lipopolysaccharide‐coated P. micros cells. This is the first study reporting a binding interaction between lipopolysaccharide and a gram‐positive bacterium. This interaction represents a new mechanism that could promote the inflammatory response during periodontitis.     

Kinetics of Th17‐related cytokine expression in experimentally induced rat periapical lesions

Th17‐related cytokines are essential factors in various pathological states, including inflammatory bone destruction. This study investigated the contribution of Th17‐related cytokines to the progress of experimentally induced rat periapical lesions. Periapical pathoses were induced by unsealed exposure of the pulp chamber of the lower first molars. A variety of immunocompetent cells, including CD68⁺ macrophages, Ia antigen⁺ cells and TCRαβ⁺ T cells, were observed in the lesions. The expression levels of Th17‐related cytokines, IL‐17 and IL‐23, and of pro‐inflammatory cytokines, IL‐1β and IL‐6, were significantly increased at 14 days (expansion stage) compared with normal periapical tissues. The expression levels of Foxp3, a regulatory T cell (Treg)‐related gene, and of IL‐10, an anti‐inflammatory cytokine, were higher at 28 days (chronic stage) than at 14 days. These findings suggest that Th17‐related cytokines may be primary contributors to the initiation of periapical bone destruction, and that lesion expansion may be regulated by anti‐inflammatory mediators.     

Porphyromonas gingivalis induces autophagy in THP‐1‐derived macrophages

Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome‐dependent degradation pathway and is a possible mechanism in inflammatory disease. Periodontitis is an inflammatory disease caused by periodontal pathogens. Porphyromonas gingivalis, an important periodontal pathogen, activates cellular autophagy to provide a replicative niche while suppressing apoptosis in endothelial cells. However, the molecular basis for a causal relationship between P. gingivalis and autophagy is unclear. This research examines the involvement of P. gingivalis in autophagy through light chain 3 (LC3) and autophagic proteins, and the role of P. gingivalis‐induced autophagy in the clearance of P. gingivalis and inflammation. To investigate the molecular mechanism of autophagy induced by P. gingivalis, PMA‐differentiated THP‐1‐derived macrophages were infected with live P. gingivalis. The P. gingivalis increased the formation of autophagosomes in a multiplicity of infection‐dependent manner, as well as autophagolysosomes. Porphyromonas gingivalis activated LC3‐I/LC3‐II conversion and increased the conjugation of autophagy‐related 5 (ATG5) –ATG12 and the expression of Beclin1. The expressions of Beclin1, ATG5–ATG12 conjugate, and LC3‐II were significantly inhibited by the presence of 3‐methyladenine, an autophagy inhibitor. Interestingly, 3‐methyladenine increased the survival of P. gingivalis and proinflammatory cytokine interleukin‐1β production. The data indicate that P. gingivalis induces autophagy in PMA‐differentiated THP‐1‐derived macrophages and in turn, macrophages eliminate P. gingivalis through an autophagic response, which can lead to the restriction of an excessive inflammatory response by downregulating interleukin‐1β production. The induction of autophagy by P. gingivalis may play an important role in the periodontal inflammatory process and serve as a target for the development of new therapies.     

Anti‐inflammatory action of cholecystokinin and melatonin in the rat parotid gland

Oral Diseases (2010) 16 , 661–667 Objective: To define the influence of cholecystokinin and melatonin on the inflammatory response of the lipopolysaccharide‐exposed rat parotid gland. Materials and methods: Bacterial lipopolysaccharide was infused retrogradely into the parotid duct. The degree of inflammation three hours postadministration was estimated from the activity of myeloperoxidase, reflecting glandular neutrophil infiltration. Results: The myeloperoxidase activity of the lipopolysaccharide‐exposed gland was 10‐fold greater than that of the contralateral gland. Combined with sulphated cholecystokinin‐8 (10 or 25 μg kg^?1, given twice intraperitoneally) or melatonin (10 or 25 mg kg^?1 × 2) the lipopolysaccharide‐induced response was elevated 4.6‐ and 3.5‐folds at the most. The cholecystokinin‐A receptor antagonist lorglumide reduced the inhibitory effect of cholecystokinin‐8, while the melatonin 2‐preferring receptor antagonist luzindole had no effect on the melatonin‐induced inhibition. Unselective nitric oxide‐synthase inhibition abolished the increase in myeloperoxidase activity, whereas inhibition of inducible or neuronal nitric oxide‐synthase (of non‐nervous origin) halved the inflammatory response. Conclusion: Some hormones may contribute to anti‐inflammatory action in salivary glands in physiological conditions. They are potential pharmacological tools for treating gland inflammation. The inflammation, as judged from the myeloperoxidase activity, was entirely dependent on nitric oxide‐synthase activity, indicating that the hormones directly or indirectly reduced the generation of nitric oxide.     

Effects of Resolvin D1 on Cell Survival and Cytokine Expression of Human Gingival Fibroblasts

Background: Tissue breakdown in periodontitis is initiated by bacteria, such as Porphyromonas gingivalis, and is caused largely by host responses. Resolvins protect the host against acute inflammation by blocking the migration of polymorphonuclear neutrophils to initiate resolution. The effects of resolvins on human gingival fibroblasts (HGFs) are unknown. This study examines the effects of resolvin D1 on HGF survival and cytokine expression when treated with or without P. gingivalis supernatant. Methods: Cytotoxicity of resolvin D1 on HGFs with or without a toxic level of P. gingivalis supernatant was measured with lactate dehydrogenase assays. Cytokine arrays were performed on HGF‐conditioned media treated with or without resolvin D1 and with or without P. gingivalis supernatant. Results: Resolvin D1 had no cytotoxic effects on HGFs at concentrations between 1 and 1,000 nM (all P > 0.05). Resolvin D1 (1,000 nM) significantly inhibited the toxic effects of 13.5% (v/v) P. gingivalis supernatant on HGFs (P = 0.002). Resolvin D1 significantly reduced the expression of interleukin (IL)‐6 (P = 0.010) and monocyte chemoattractant protein (MCP)‐1 (P = 0.04) in untreated fibroblasts. P. gingivalis (10%) supernatant significantly increased the expression levels of granulocyte‐macrophage colony‐stimulating factor (CSF), granulocyte CSF, growth‐regulated oncogene (GRO), IL‐5, IL‐6, IL‐7, IL‐8, IL‐10, MCP‐1, MCP‐2, MCP‐3, and monokine induced by γ‐interferon. Resolvin D1 significantly reduced the expression of GRO (P = 0.04), marginally reduced the levels of MCP‐1 (P = 0.10), and marginally increased the levels of transforming growth factor (TGF)‐β1 (P = 0.07) from HGFs treated with P. gingivalis supernatant. Conclusions: Resolvin D1 altered the cytotoxicity of P. gingivalis supernatant on HGFs. Resolvin D1 significantly reduced GRO, marginally reduced MCP‐1, and marginally increased TGF‐β1 from P. gingivalis–treated HGFs, which could alter the ability of P. gingivalis to induce inflammation.     

Regulation of inflammation by lipid mediators in oral diseases

Lipid mediators (LM) of inflammation are a class of compounds derived from ω‐3 and ω‐6 fatty acids that play a wide role in modulating inflammatory responses. Some LM possess pro‐inflammatory properties, while others possess proresolving characteristics, and the class switch from pro‐inflammatory to proresolving is crucial for tissue homeostasis. In this article, we review the major classes of LM, focusing on their biosynthesis and signaling pathways, and their role in systemic and, especially, oral health and disease. We discuss the detection of these LM in various body fluids, focusing on diagnostic and therapeutic applications. We also present data showing gender‐related differences in salivary LM levels in healthy controls, leading to a hypothesis on the etiology of inflammatory diseases, particularly Sjögren's syndrome. We conclude by enumerating open areas of research where further investigation of LM is likely to result in therapeutic and diagnostic advances.     

Immunologic environment influences macrophage response to Porphyromonas gingivalis

Macrophages adapt both phenotypically and functionally to the cytokine balance in host tissue microenvironments. Recent studies established that macrophages contribute an important yet poorly understood role in the development of infection‐elicited oral bone loss. We hypothesized that macrophage adaptation to inflammatory signals encountered before pathogen interaction would significantly influence the subsequent immune response of these cells to the keystone oral pathobiont Porphyromonas gingivalis. Employing classically activated (M1) and alternatively activated (M2) murine bone‐marrow‐derived macrophage (BMDMø), we observed that immunologic activation of macrophages before P. gingivalis challenge dictated phenotype‐specific changes in the expression of inflammation‐associated molecules important to sensing and tuning host response to bacterial infection including Toll‐like receptors 2 and 4, CD14, CD18 and CD11b (together comprising CR3), major histocompatibility complex class II, CD80, and CD86. M2 cells responded to P. gingivalis with higher expression of tumor necrosis factor‐α, interleukin‐6, monocyte chemoattractant protein‐1, macrophage inflammatory protein‐1α, regulated on activation normal T cell expressed and secreted, and KC than M1 cells. M1 BMDMø expressed higher levels of interleukin‐10 to P. gingivalis than M2 BMDMø. Functionally, we observed that M2 BMDMø bound P. gingivalis more robustly than M1 BMDMø. These data describe an important contribution of macrophage skewing in the subsequent development of the cellular immune response to P. gingivalis.     

补体5a及其受体和效应通路与牙周炎的关系

补体（C）5a与其受体（C5aR）结合后,可诱导中．性粒细胞、巨噬细胞等向炎症部位聚集,诱导炎性递质的生成。CD88和C5L2为目前已知的两种C5aR,在中性粒细胞、巨噬细胞和不成熟树突细胞上都有表达,可能促进炎症反应的发生。C5a可能通过细胞外信号调节激酶1、2以及P38促丝裂原激活蛋白激酶通路抑制中性粒细胞程序性死亡发挥促炎作用。抑制C5a与C5aR之间的相互作用,在一定程度上可以抑制中性粒细胞的活化、活性氧的释放以及那基质金属蛋白酶的生成,从而减轻炎症和组织损伤。进一步了解c5a及其受体在牙周炎发生发展中的作用机制可为牙周炎的治疗提供又一新途径。     

TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice

Oral Diseases (2012) 18 , 365–374 Objective: Patients with Sjögren’s syndrome (SS) show aberrant expression of the B cell‐related mediators, B cell‐activating factor (BAFF), and a proliferation‐inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. Material and Methods: A recombinant serotype 2 adeno‐associated virus (rAAV2) encoding TACI‐Fc was constructed, and its efficacy was tested in the SGs of non‐obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. Results: AAV2‐TACI‐Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD⁺ cells and CD138⁺ cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2‐TACI‐Fc‐treated mice. Salivary flow was unaffected. Conclusion: Although local expression of soluble TACI‐Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI‐Fc can provide a satisfying treatment for the clinical symptoms of patients.