Human anti-Human CCL5 recombinant monoclonal antibody, PE

This study aimed to explore crucial genes that contribute to the development of rheumatoid arthritis (RA). Three GSE77298, GSE55457, and GSE55235 data sets were used to analyze the differentially expressed genes (DEGs) between RA synovial membrane tissue samples and normal synovial membrane tissue samples. Then, the functional enrichment analysis and protein-protein interactions (PPIs) construction were performed for DEGs. Subsequently, submodule analysis and regulatory network that contained transcription factors (TFs), microRNAs, and their targets were conducted. Finally, small-molecule drugs related to the DEGs were predicted. A total of 173 upregulated and 54 downregulated DEGs identified in at least 2 of 3 data sets. TYROBP, CTSS, MMP9, CXCR4, and CXCL10 were both highlighted in the PPI and submodule networks. In addition, miR-101, IRF1 TF, DUSP1, and CXCR4 had high degree in the regulatory network, and regulation pairs of miR-101-DUSP1 and IRF1 TF-CXCR4 were obtained. Drugs such as alemtuzumab and marimastat were negatively related to expression of the DEGs and might be useful drugs for RA treatment. In addition, most DEGs were involved in innate immune response (e.g., TYROBP, CCL5, CXCL10, FCGR1A, and FCGR3B) and phagosome pathway (e.g., CTSS). We suggested that miR-101 that regulated DUSP1, IRF1 TF that regulated CXCR4, as well as DEGs as TYROBP and CTSS might contribute to the RA pathogenesis. In addition, anti-inflammatory agent alemtuzumab and matrix metalloproteinase inhibitor marimastat might be useful drugs for RA treatment through functioning on their target genes.

Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10, before EEA1 and Rab5 recruitment to early macropinosomes occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, and LRRK2-phosphorylation of Rab10 potently blocks EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 overexpression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppress the maturation of macropinosome-derived CCR5-loaded signaling endosomes that are critical for CCL5-induced immunological responses that include Akt activation and chemotaxis. These data support a novel signaling axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast recycling to promote PI3K-Akt immunological responses.