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AimThe aim of this study was to investigate whether Dectin-1 influences the immune-inflammatory response in A. fumigatus keratitis by modulating macrophage polarization.Methods1. The models of 1-day, 3-day, and 5-day of fungal keratitis were established in SPF C57BL/6 mice after stimulation by A. fumigatus. Dectin-1 agonist (curdlan) and antagonist (laminaran) were injected separately in the mouse subconjunctivae for 1 day in the established mouse model of A. fumigatus keratitis; PBS was used as the control. Inflammation of the mouse cornea was observed under a slit lamp to obtain a clinical score. 2. The expression of M1 (TNF-α, INOS, IL-6, IL-12) and M2 (Arg-1, IL-10, Fizz-1, Ym-1) cytokine-encoding mRNAs was quantified by RT-PCR. 3. Changes in the number of macrophages and expression of M1 and M2 macrophages in mouse corneas detected by immunofluorescence and flow cytometry. 4. Pre-treatment of RAW264.7 cells with MAPK cell signaling pathway inhibitors SB203580 (p38 inhibitor, 10µM), U0126 (ERK inhibitor, 20µM), SP600125 (JNK inhibitor, 10µM) and DMSO separately for 2 h, and stimulated by A. fumigatus for 12 h. Changes in the mRNA expression of M1 and M2 cytokines in the macrophages were quantified by RT-PCR.Results1. With curdlan pre-treatment, mouse corneal inflammation worsened, and the clinical score increased after infection. In contrast, in the laminaran pre-treated group, corneal inflammation was alleviated and the clinical score decreased significantly compared to the PBS group after infection. 2. Compared with the control group, the expression levels of macrophage phenotype-related M1 and M2 cytokine mRNAs increased significantly 1, 3, and 5 days after A. fumigatus infected the corneas of mice. 3. With curdlan pre-treatment, the expression of mRNAs encoding M1 cytokines increased, while those encoding M2 cytokines decreased in the cornea compared to the PBS group. In contrast, after infection, mRNA levels for M1 cytokines decreased significantly and those for M2 cytokines increased in the cornea of the laminaran pre-treated group compared to the PBS group. 4. The number of macrophages in the corneal stroma of mice in the curdlan pretreatment group increased significantly compared with the PBS group, while in the laminaran pretreatment group this number decreased significantly. 5. The results of flow cytometry showed that after 3 days of mouse corneal A. fumigatus infection, the number of macrophages in the mouse A. fumigatus model in the curdlan pretreatment group was increased (10.4%) and the number of macrophages in the mouse A. fumigatus model in the laminaran pretreatment group (6.31%), when compared with the AF+FBS group (7.91%). The proportion of M1-type macrophages was increased in the curdlan pretreated group (55.6%) compared to the AF+FBS group (51.2%), the proportion of laminaran pretreatment group had a decreased proportion of M1-type macrophages (46.8%); while M2-type macrophages were the opposite of M1-type: the proportion of M2-type macrophages was 49.2% in the AF+FBS group, the proportion of M2-type macrophages was decreased in the curdlan pretreatment group (44.0%), and the proportion of M2-type macrophages was increased in the laminaran pretreatment group (53.5%). 6. Expression of M1 and M2 cytokine-encoding mRNAs decreased and increased, respectively, after infection, in the RAW264.7 cells pre-treated with MAPK pathway inhibitors, compared to the control.ConclusionIn a mouse model of A. fumigatus keratitis, Dectin-1 can affect macrophage recruitment and polarization, may regulate macrophage phenotype-associated factor changes through the MAPK signaling pathway.

The East Asian summer monsoon (EASM) is unique among monsoon systems that it features meridional evolution of the summer monsoon. In this study, we evaluate the performances of a Variable-Resolution Community Earth System Model (VR-CESM) regionally refined over eastern China (14 km) in reproducing the seasonal evolution of EASM precipitation over China. Compared with reference datasets, VR-CESM shows better performance than the corresponding globally uniform coarse-resolution model CESM (quasi-uniform 1°), especially over western China where complex local topography exists. The northward monsoon migration is closely related to low-level southerly flows and vertical moisture advection, which are more reasonably simulated in VR-CESM. The four critical timings of the EASM (monsoon onset, withdrawal, peak, and duration) are also better captured in VR-CESM than in CESM. The corresponding spatial Pearson correlation coefficients of the four critical timings with respect to reference datasets are about 0.1 higher in VR-CESM than those in CESM. Both models are most accurate in simulating monsoon onset and least accurate at simulating the monsoon peak. The overestimated zonal thermal contrast in CESM is responsible for the earlier monsoon onset and excessive precipitation in September over the Yangtze River valley. Finer resolution in VR-CESM, especially over the Tibetan Plateau (TP), appears to be a main factor in simulating better zonal thermal contrast and seasonal evolution of the EASM.