Contribution of Interleukin-17A to Retinal Degenerative Diseases.

Retinal degenerative diseases are a leading cause of vision loss and blindness throughout the world, characterized by chronic and progressive loss of neurons and/or myelin. One of the common features of retinal degenerative diseases and central neurodegenerative diseases is chronic neuroinflammation. Interleukin-17A (IL-17A) is the cytokine most closely related to disease in its family. Accumulating evidence suggests that IL-17A plays a key role in human retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and glaucoma. This review aims to provide an overview of the role of IL-17A participating in the pathogenesis of retinal degenerative diseases, which may open new avenues for potential therapeutic interventions.

Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases.

Periodontitis is a chronic inflammatory and destructive disease caused by periodontal microbial infection and mediated by host immune response. As the main cause of loosening and loss of teeth in adults, it is considered to be one of the most common and serious oral diseases in the world. The co-existence of periodontitis and systemic chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, diabetes and so on is very common. It has been found that interleukin-17A (IL-17A) secreted by various innate and adaptive immune cells can activate a series of inflammatory cascade reactions, which mediates the occurrence and development of periodontitis and related systemic chronic inflammatory diseases. In this work, we review the role of IL-17A in the pathomechanisms of periodontitis and related systemic chronic inflammatory diseases, and briefly discuss the therapeutic potential of cytokine targeted agents that modulate the IL-17A signaling. A deep understanding of the possible molecular mechanisms in the relationship between periodontitis and systemic diseases will help dentists and physicians update their clinical diagnosis and treatment ideas.

IL-17A promotes vascular calcification in an ex vivo murine aorta culture.

BACKGROUND: Vascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system. METHODS: Thoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses. RESULTS: IL-1ß, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent. CONCLUSIONS: IL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.

Non-immune functions of inflammatory cytokines targeted by anti-psoriatic biologics: a review.

PURPOSE: Psoriasis is an inflammatory disease characterized by skin thickening with silvery white desquamation due to dysregulated inflammatory pathways and elevated levels of inflammatory cytokines. Biologic agents targeting these inflammatory cytokines have brought about significant improvement in clearing psoriatic lesions in patients with moderate-to-severe psoriasis. Moreover, biologics exert both beneficial and detrimental effects on comorbidities in psoriasis, which include increased risk of cardiovascular events, metabolic syndrome, among other conditions. However, non-immune functions of cytokines targeted by biologics, and, hence, the potential risks and benefits of biologics for psoriasis to different organs/systems and comorbidities, have not been well elucidated. RESULTS: This review summarizes current understanding of the pathogenesis of psoriasis-related comorbidities and emerging discoveries of roles of cytokines targeted in psoriasis treatment, including tumor necrosis factor α and interleukins 12, 23, and 17, aiming to complete the safety profile of each biologics and provide therapeutic implications on psoriasis-related comorbidities, and on diseases involving other organs or systems.

Novel role for caspase recruitment domain family member 14 and its genetic variant rs11652075 in skin filaggrin homeostasis.

BACKGROUND: Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression. OBJECTIVE: We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences. METHODS: A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies. RESULTS: The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children's skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype. CONCLUSIONS: Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.

Interleukin-17A in Alzheimer's Disease: Recent Advances and Controversies.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that mainly affects older adults. Although the global burden of AD is increasing year by year, the causes of AD remain largely unknown. Numerous basic and clinical studies have shown that interleukin-17A (IL-17A) may play a significant role in the pathogenesis of AD. A comprehensive assessment of the role of IL-17A in AD would benefit the diagnosis, understanding of etiology and treatment. However, over the past decade, controversies remain regarding the expression level and role of IL-17A in AD. We have incorporated newly published researches and point out that IL-17A expression levels may vary along with the development of AD, exercising different roles at different stages of AD, although much more work remains to be done to support the potential role of IL-17A in AD-related pathology. Here, it is our intention to review the underlying mechanisms of IL-17A in AD and address the current controversies in an effort to clarify the results of existing research and suggest future studies.

The role of IL-17 and anti-IL-17 agents in the immunopathogenesis and management of autoimmune and inflammatory diseases.

Interleukin-17 (IL-17) is a proinflammatory cytokine involved in chronic inflammation occurring during the pathogenesis of allergy, malignancy, and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis. IL-17 is produced by multiple cell types of adaptive and innate immunity, including T helper 17 cells, CD8 + T cells, γδ T cells, natural killer T cells, and innate lymphoid cells. Monoclonal antibodies (mAbs) targeting IL-17 and/or IL-17R would be a potential approach to study this therapeutic tool for these diseases. In the current review, we aimed to highlight the characteristics of IL-17 and its important role in the pathogenesis of related diseases. Critical evaluation of the mAbs targeting IL-17A and IL-17 receptors (e.g., Ixekizumab, Secukinumab, and Brodalumab) in various immune-mediated diseases will be provided, and finally, their clinical efficacy and safety will be reported.

TH17 cells and corticosteroid insensitivity in severe asthma.

Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated TH17 cell immune responses. TH17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of TH17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma.

Identification and Clinical Validation of Key Extracellular Proteins as the Potential Biomarkers in Relapsing-Remitting Multiple Sclerosis.

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mediated by autoimmunity. No objective clinical indicators are available for the diagnosis and prognosis of MS. Extracellular proteins are most glycosylated and likely to enter into the body fluid to serve as potential biomarkers. Our work will contribute to the in-depth study of the functions of extracellular proteins and the discovery of disease biomarkers. Methods: MS expression profiling data of the human brain was downloaded from the Gene Expression Omnibus (GEO). Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases. GO and KEGG were used to analyze the function and pathway of EP-DEGs. STRING, Cytoscape, MCODE and Cytohubba were used to construct a protein-protein interaction (PPI) network and screen key EP-DEGs. Key EP-DEGs levels were detected in the CSF of MS patients. ROC curve and survival analysis were used to evaluate the diagnostic and prognostic ability of key EP-DEGs. Results: We screened 133 EP-DEGs from DEGs. EP-DEGs were enriched in the collagen-containing extracellular matrix, signaling receptor activator activity, immune-related pathways, and PI3K-Akt signaling pathway. The PPI network of EP-DEGs had 85 nodes and 185 edges. We identified 4 key extracellular proteins IL17A, IL2, CD44, IGF1, and 16 extracellular proteins that interacted with IL17A. We clinically verified that IL17A levels decreased, but Del-1 and resolvinD1 levels increased. The diagnostic accuracy of Del-1 (AUC: 0.947) was superior to that of IgG (AUC: 0.740) with a sensitivity of 82.4% and a specificity of 100%. High Del-1 levels were significantly associated with better relapse-free and progression-free survival. Conclusion: IL17A, IL2, CD44, and IGF1 may be key extracellular proteins in the pathogenesis of MS. IL17A, Del-1, and resolvinD1 may co-regulate the development of MS and Del-1 is a potential biomarker of MS. We used bioinformatics methods to explore the biomarkers of MS and validated the results in clinical samples. The study provides a theoretical and experimental basis for revealing the pathogenesis of MS and improving the diagnosis and prognosis of MS.

STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer.

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.

Interleukin-25: New perspective and state-of-the-art in cancer prognosis and treatment approaches.

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell-derived factors such as cytokines and chemokines plays a central role. IL-25, as a member of the IL-17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL-25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL-25 exerts a tumor-suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor-supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type-2 immune responses. Since IL-25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL-25-based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL-25 has a tumor-suppressive function, employing IL-25-enhancing approaches, such as Virulizin® and dihydrobenzofuran administration, has potentially inhibited tumor cell growth. On the other hand, in the case of IL-25-dependent tumor progression, using IL-25 blocking methods, including anti-IL-25 antibodies, might be a complementary approach to the other anticancer agent. Collectively, it is hoped, IL-25 might be a promising target in cancer treatment.

Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro.

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.

A Partial Picture of the Single-Cell Transcriptomics of Human IgA Nephropathy.

The molecular mechanisms underlying renal damage of IgA nephropathy (IgAN) remain incompletely defined. Here, single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from IgAN and control subjects to define the transcriptomic landscape at single-cell resolution. We presented a comprehensive scRNA-seq analysis of human renal biopsies from IgAN. We showed for the first time that IgAN mesangial cells displayed increased expression of several novel genes including MALAT1, GADD45B, SOX4, and EDIL3, which were related to cell proliferation and matrix accumulation. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. Furthermore, we compared the results of 4 IgAN patients with the published scRNA-Seq data of healthy kidney tissues of three human donors in order to further validate the findings in our study. The results also verified that the overexpressed genes in tubule cells from IgAN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. The receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. IgAN patients with overt proteinuria displayed elevated genes participating in several signaling pathways compared with microproteinuria group. It needs to be mentioned that based on number of mesangial cells and other kidney cells analyzed in this study, the results of our study are preliminary and needs to be confirmed on larger number of cells from larger number of patients and controls in future studies. Therefore, these results offer new insight into pathogenesis and identify new therapeutic targets for IgAN.

Exposure to biomass smoke induces pulmonary Th17 cell differentiation by activating TLR2 on dendritic cells in a COPD rat model.

Almost three billion people in developing countries are exposed to biomass smoke (BS), which predisposes them to developing chronic obstructive pulmonary disease (COPD). COPD is associated with abnormal innate and adaptive immune responses in the lungs and systemic circulation, but the mechanisms underlying BS-COPD development are uncertain. We investigated the role of dendritic cells (DCs) and interleukin (IL)-17A in BS-COPD. We investigated T helper cell responses in the BS-exposed COPD rat model by flow cytometry, quantitative PCR, and enzyme-linked immunosorbent assays. We conducted ex vivo experiments to determine which antigen-presenting cells induce Th17 cell responses. We evaluated the in vitro effects of BS-related particulate matter (BRPM) (2.5 µm) on the function of bone marrow-derived dendritic cells (BMDCs). We found that BS exposure enhanced Th17 responses in the lungs of the COPD-modelled rats, and the stimulated DCs (but not the macrophages) were sufficient to induce naïve CD4 + T cells to produce IL-17A in ex vivo experiments. BRPM significantly enhanced the maturation and activation of DCs through Toll-like receptor 2 (TLR2), but not TLR4, and induced Th17 responses. Therefore, BS activated lung DCs through TLR2, which led to Th17 responses and emphysema in the rats. This process is possibly therapeutically targetable.

[Interleukin-17A: Possible mediator and therapeutic target in hypertension]. / Interleuquina-17A: posible mediador y diana terapéutica en la hipertensión.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immune system, predominantly Th17 lymphocytes and γδ lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and target organ damage. Studies in mice have shown that IL-17A increases blood pressure, probably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are already elevated in patients with mild or moderate hypertension. Preclinical studies on arterial hypertension have detected IL-17A-producing cells in target organs such as the heart, vessels and kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17 lymphocytes and γδ lymphocytes that express IL-17A. In addition, in experimental models of hypertension, blocking IL-17A by genetic strategies, or using neutralising antibodies, lowers blood pressure by acting on the vascular wall and tubule sodium transport and reduces damage to target organs. As a whole, the data presented in this review suggest that IL-17A participates in the regulation of blood pressure and in the genesis and maintenance of arterial hypertension, and may constitute a therapeutic target in the future.

T Helper 17 Response to Severe Acute Respiratory Syndrome Coronavirus 2: A Type of Immune Response with Possible Therapeutic Implications.

The initial immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) includes an interferon-dependent antiviral response. A late and uncontrolled inflammatory response characterized by high activity of proinflammatory cytokines and the recruitment of neutrophils and macrophages develops in predisposed individuals and is potentially harmful in some cases. Interleukin (IL)-17 is one of the many cytokines released during coronavirus disease 2019 (COVID-19). IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung, and are heavily involved in the pathogenesis of COVID-19. During the infection T helper 17 (Th17) cells and IL-17-related pathways are associated with a worse outcome of the disease. All these have practical consequences considering that some drugs with therapeutic targets related to the Th17 response may have a beneficial effect on patients with SARS-CoV-2 infection. Herein, we present the arguments underlying our assumption that blocking the IL-23/IL-17 axis using targeted biological therapies as well as drugs that act indirectly on this pathway such as convalescent plasma therapy and colchicine may be good therapeutic options.

Existence of Staphylococcus aureus correlates with the progression of extramammary Paget's disease: potential involvement of interleukin-17 and M2-like macrophage polarization.

BACKGROUND: The microbiome plays an important role in the tumour microenvironment (TME). OBJECTIVES: In this study, we investigated the clinical significance of the microbiota in extramammary Paget's disease (EMPD). MATERIALS & METHODS: Patients with EMPD, treated between March 2007 and September 2019 at Kumamoto University Hospital, were investigated retrospectively. Inclusion criteria included: histological diagnosis of EMPD, inspection of the bacterial culture of the cancer lesion using swab sampling, and availability of sufficient tissue in paraffin blocks for immunohistochemistry. For the latter, primary antibodies against IL-17, CD163 and ionized calcium-binding adapter molecule 1 (Iba1) were used. RESULTS: Bacterial cultures of the cancer lesion revealed that Staphylococcus aureus (S. aureus) was highly prevalent in EMPD patients, with dermal invasion or lymph node metastasis, compared to patients without these findings. Furthermore, the number of IL-17-positive cells and CD163-positive M2-like macrophages (pro-tumour macrophages) were increased in EMPD tissues with S. aureus. Moreover, the number of IL-17-producing cells in EMPD tissues positively correlated with the accumulation of CD163-positive M2-like macrophages. In addition, the percentage of CD163-positive cells within Iba-1-positive macrophages (total macrophages) was also significantly elevated in EMPD tissues with S. aureus. CONCLUSION: Based on these findings, S. aureus may exacerbate the pathological condition of EMPD via the accumulation of IL-17 and M2-like macrophages.

Neutrophil-Derived IL-17 Promotes Ventilator-Induced Lung Injury via p38 MAPK/MCP-1 Pathway Activation.

Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation and can severely affect health. VILI appears to involve excessive inflammatory responses, but its pathogenesis has not yet been clarified. Since interleukin-17 (IL-17) plays a critical role in the immune system and the development of infectious and inflammatory diseases, we investigated here whether it plays a role in VILI. In a mouse model of VILI, mechanical ventilation with high tidal volume promoted the accumulation of lung neutrophils, leading to increased IL-17 levels in the lung, which in turn upregulated macrophage chemoattractant protein-1 via p38 mitogen-activated protein kinase. Depletion of neutrophils decreases the production IL-17 in mice and inhibition of IL-17 significantly reduced HTV-induced lung injury and inflammatory response. These results were confirmed in vitro using RAW264.7 macrophage cultures. Our results suggest that IL-17 plays a pro-inflammatory role in VILI and could serve as a new target for its treatment.

Triggering Receptor Expressed on Myeloid Cells-2 Protects Aged Mice Against Sepsis by Mitigating the IL-23/IL-17A Response.

BACKGROUND: Advancing age is an independent predictor of mortality in septic patients. Recent animal studies were unable to reflect this clinical pathophysiological process, largely hampering the development of new efficacious therapies. Triggering receptor expressed on myeloid cells-2 (TREM-2) is a novel immune regulator with multiple activities. However, very little is known about the regulatory role of TREM-2 in sepsis upon aging. METHODS: Blood samples were collected from septic patients within 24 h after intensive care unit admission. The patients were preselected into two groups based on the age (age with ≥60 years old and age with <60 years old). Sepsis in aged mice was induced by cecal ligation and puncture. The expression of TREM-2 was evaluated in septic patients and aged septic mice. Aged macrophages overexpressing TREM-2 and green fluorescent protein (GFP) were administered to aged septic mice after cecal ligation and puncture. Survival rate was monitored, and bacterial load and inflammatory mediators levels were evaluated. In vivo IL-23 function was blocked using appropriate monoclonal antibodies. RESULTS: The expression levels of TREM-2 were downregulated in both aged septic patients and aged septic mice. The administration of TREM-2-overexpressing macrophages significantly prolonged survival and alleviated organ injury in the aged septic mice. The protective effect did not affect host bacterial burden, but markedly inhibited the host IL-17A response, as determined by a multiplex cytokine assay. Screening the expression of IL-17A-related activating factors revealed that the IL-23 level in TREM-2-overexpressing macrophages was significantly lower than that in GFP-expressing macrophages. Blocking IL-23 after the administration of GFP-expressing macrophages protected aged mice against sepsis. CONCLUSIONS: TREM-2 prolonged survival of aged mice from sepsis by finely modulating the IL-23/IL-17A immune pathway. These results provide previously unidentified mechanistic insight into immune regulation by TREM-2 and new therapeutic targets in sepsis upon aging.