Protease inhibitors regulate various biological processes and prevent host tissue/organ damage. Specific inhibition/regulation of proteases is clinically valuable for treating several diseases. Psoriasis affects the skin in the limbs and scalp of the body, and the contribution of cysteine and serine proteases to the development of skin inflammation is well documented. Cysteine protease inhibitors from ticks have high specificity, selectivity, and affinity to their target proteases and are efficient immunomodulators. However, their potential therapeutic effect on psoriasis pathogenesis remains to be determined. Therefore, we tested four tick cystatins (Sialostatin L, Sialostatin L2, Iristatin, and Mialostatin) in the recently developed, innate immunity-dependent mannan-induced psoriasis model. We explored the effects of protease inhibitors on clinical symptoms and histological features. In addition, the number and percentage of immune cells (dendritic cells, neutrophils, macrophages, and γδT cells) by flow cytometry, immunofluorescence/immunohistochemistry and, the expression of pro-inflammatory cytokines (TNF-a, IL-6, IL-22, IL-23, and IL-17 family) by qPCR were analyzed using skin, spleen, and lymph node samples. Tick protease inhibitors have significantly decreased psoriasis symptoms and disease manifestations but had differential effects on inflammatory responses and immune cell populations, suggesting different modes of action of these inhibitors on psoriasis-like inflammation. Thus, our study demonstrates, for the first time, the usefulness of tick-derived protease inhibitors for treating skin inflammation in patients.

• Keywords
• autoimmune disease, immune responses, protease inhibitors, psoriasis, tick,
• MeSH
• Dermatitis * MeSH
• Endopeptidases MeSH
• Cysteine Proteinase Inhibitors MeSH
• Protease Inhibitors MeSH
• Humans MeSH
• Mannans MeSH
• Immunity, Innate MeSH
• Peptide Hydrolases MeSH
• Psoriasis * chemically induced   drug therapy   MeSH
• Inflammation drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Endopeptidases MeSH
• Cysteine Proteinase Inhibitors MeSH
• Protease Inhibitors MeSH
• Mannans MeSH
• Peptide Hydrolases MeSH

Extracellular vesicles are thought to facilitate pathogen transmission from arthropods to humans and other animals. Here, we reveal that pathogen spreading from arthropods to the mammalian host is multifaceted. Extracellular vesicles from Ixodes scapularis enable tick feeding and promote infection of the mildly virulent rickettsial agent Anaplasma phagocytophilum through the SNARE proteins Vamp33 and Synaptobrevin 2 and dendritic epidermal T cells. However, extracellular vesicles from the tick Dermacentor andersoni mitigate microbial spreading caused by the lethal pathogen Francisella tularensis. Collectively, we establish that tick extracellular vesicles foster distinct outcomes of bacterial infection and assist in vector feeding by acting on skin immunity. Thus, the biology of arthropods should be taken into consideration when developing strategies to control vector-borne diseases.

• MeSH
• Anaplasma phagocytophilum pathogenicity   MeSH
• Bacterial Infections immunology   metabolism   MeSH
• Cell Line MeSH
• Arthropods metabolism   microbiology   physiology   MeSH
• Dermacentor metabolism   microbiology   physiology   MeSH
• Extracellular Vesicles metabolism   ultrastructure   MeSH
• Francisella tularensis pathogenicity   MeSH
• Gene Ontology MeSH
• Intravital Microscopy MeSH
• Ticks metabolism   microbiology   MeSH
• Ixodes metabolism   microbiology   physiology   MeSH
• Skin immunology   microbiology   parasitology   MeSH
• Humans MeSH
• Vesicle-Associated Membrane Protein 2 metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• R-SNARE Proteins metabolism   MeSH
• Proteomics MeSH
• T-Lymphocytes metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Microscopy, Electron, Transmission MeSH
• Inflammation immunology   metabolism   parasitology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Vesicle-Associated Membrane Protein 2 MeSH
• R-SNARE Proteins MeSH

Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.

• MeSH
• Anaplasma phagocytophilum immunology   MeSH
• Dinoprostone immunology   MeSH
• Ehrlichiosis immunology   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Immunoblotting MeSH
• Inflammasomes immunology   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Apoptosis Regulatory Proteins immunology   MeSH
• Calcium-Binding Proteins immunology   MeSH
• Receptors, Prostaglandin E, EP3 Subtype immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Dinoprostone MeSH
• Inflammasomes MeSH
• Ipaf protein, mouse MeSH Browser
• Apoptosis Regulatory Proteins MeSH
• Calcium-Binding Proteins MeSH
• Receptors, Prostaglandin E, EP3 Subtype MeSH