Multi-organ single cell analysis of a mouse model of collagen-induced arthritis [subseries1]

Prioratization of disease associated mechanisms in immune-mediated inflammatory diseases (IMIDs) is complicated by altered interactions across multiple organs and cell types. We have adressed these challenges by analyzing a multi-organ multicellular disease model (MO-MCDM) of a mouse IMID model, namely collagen-induced arthritis (CIA). For all the five organs (joint, lung, muscle, skin, and spleen) we found highly complex and heterogenous expression changes due to disease, although, macroscopic and microscopic signs of inflammation could only be seen in joints. Based on the MO-MCDM, predicted molecular interactions within and between organs could be identified. The model supported that inflammation was switched on or off in different organs, by an altered balande between pro- and anti-inflammatory upstream regulators and downstream pathways. This on/off switch was validated in human IMIDs, by analyses of publically available data from 32 different samples of 10 different IMIDs. Additionally, it showed consistency with a general characteristic of both CIA and human IMIDs, namely variable organ involvement in disease. Overall design: Organ samples were taken from male DBA1/J 6 CIA and 4 healthy mice. The CIA mice were immunized with 100 µg (50µL) bovine collagen II (BC-II, Chondrex, USA) emulsified with 50µL Complete Freund's Adjuvant (CFA) (Sigma-Aldrich, USA) in 1:1 ratio, via intradermal injection near the base of the tail. A booster immunization was administered on day 20 with 100 µg of BC-II emulsion (prepared with 1:1 incomplete Freund's adjuvant (IFA)) and injected at the base of the tail. The severity of each arthritic limb was scored on 0-4 scale, 0: Normal, 1: Swelling and redness in one digit, 2: Swelling and redness in more than one digits or swelling and redness in one digit, wrist joint and ankle, 3: Swelling and redness present in paw and digits, 4: maximum inflammation of limb involving all joints and digits. The total arthritis score was the sum score from all four limbs.