Inhibition of TREM-1 and Dectin-1 Alleviates the Severity of Fungal Keratitis by Modulating Innate Immune Responses

Abstract

PurposeTo explore the possibility that inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1) and Dendritic cell-associated C-type lectin-1(Dectin-1) could modulate the innate immune response and alleviate the severity of corneal fungal keratitis.MethodTREM-1 and Dectin-1 expression was detected in fungus-infected human corneal specimens by real-time PCR. C57BL/6 (B6) mice were injected with Aspergillus fumigatus and divided into 4 groups that received subconjunctival injections of PBS and IgG as a control (group I), mTREM-1/IgG fusion protein (group II), the soluble β-glucan antagonist laminarin (group III), or mTREM-1/Fc and laminarin (group IV). Corneal virulence was evaluated based on clinical scores. TREM-1 and Dectin-1 mRNA levels were assayed using real-time PCR. The distribution patterns of TREM-1, Dectin-1 and cellular infiltrates in fungus-infected corneas were examined by immunohistochemistry. Moreover, changes in T Helper Type1 (Th1)-/ T Helper Type1 (Th2)- type cytokines and proinflammatory cytokines were measured.ResultsThe expression of TREM-1 and Dectin-1 increased significantly and correlated positively with the progression of fungal keratitis. Most infiltrated cells were neutrophils and secondarily macrophages in infected cornea. The clinical scores decreased after interfering with TREM-1 and Dectin-1 expression in infected mouse corneas. Levels of Th1-type cytokines including interleukin-12 (IL-12), IL-18 and interferon-γ (IFN-γ) were decreased in the cornea, while the levels of Th2-type cytokines, including IL-4, IL-5 and IL-10, showed obvious increases.ConclusionTREM-1 and Dectin-1 function concurrently in the corneal innate immune response by regulating inflammatory cytokine expression in fungal keratitis. Inhibition of TREM-1 and Dectin-1 can alleviate the severity of corneal damage by downregulating the excessive inflammatory response.

Blocking triggering receptor expressed on myeloid cells-1 attenuates lipopolysaccharide-induced acute lung injury via inhibiting NLRP3 inflammasome activation

“…TREM-1 activation can amplify TLRs and NLRs signaling to promote the production of pro-inflammatory cytokines, degranulation of neutrophils, and phagocytosis 111213. Depletion or blocking TREM-1 has shown protective effects in sepsis, ischemia-reperfusion, pancreatitis, inflammatory bowel diseases, Fungal Keratitis and arthritis14151617181920. Our previous study found that the expression of TREM-1 in LPS-induced ALI mice lung and macrophages are significantly increased, suggesting an important role of TREM-1 in ALI2122.…”

Genome-Wide Bimolecular Fluorescence Complementation-Based Proteomic Analysis of Toxoplasma gondii ROP18’s Human Interactome Shows Its Key Role in Regulation of Cell Immunity and Apoptosis

“…Following the infection of T. gondii , innate cells, including macrophages, dendritic cells, and neutrophils, are recruited to the sites of infection, producing proinflammatory cytokines, phagocytizing the parasites, or generating reactive chemical substances in order to inhibit the replication and dissemination of the parasites ( 46 – 49 ). Human NPY, LGALS1, S100A12, SAA1, and TREM1 have been reported as regulators of innate immunity, modulating the innate immune functions by controlling the innate cells physiology and cytokines release ( 50 – 55 ). In this study, NPY, LGALS1, and TREM1 were found as targets of ROP18 I , and S100A12, SAA1, and TREM1 were targets of ROP18 II .…”

Protective Effect of Galectin-1 duringHistoplasma capsulatumInfection Is Associated with Prostaglandin E2and Nitric Oxide Modulation

“…Moreover, the presence of high number of neutrophils may be a major source of IL-12 detected in the lung from infected-Lgals1 −/− mice, as neutrophils have been reported to produce IL-12 [ 54 ]. Curiously, inhibition of dectin-1 expression, a host receptor for fungal beta-glucan, reduces the severity of fungus infection and its effect was associated with decrease of proinflammatory cytokines, including IL-12, and neutrophil infiltration [ 55 ]. Furthermore, it is known that proinflammatory cytokines, including IL-12 [ 32 , 34 , 56 , 57 ], are essential for host defense against H. capsulatum .…”