Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

Abstract

21The identification of lymphocyte subsets with non-overlapping 22 effector functions has been pivotal to the development of targeted 23 therapies in immune mediated inflammatory diseases (IMIDs). 24 However it remains unclear whether fibroblast subclasses with non-25 overlapping functions also exist and are responsible for the wide 26 variety of tissue driven processes observed in IMIDs such as 27 inflammation and damage . Here we identify and describe the biology 28 of distinct subsets of fibroblasts responsible for mediating either 29 inflammation or tissue damage in arthritis. We show that deletion of 30 FAPα+ synovial cells suppressed both inflammation and bone 31 erosions in murine models of resolving and persistent arthritis. Single 32 cell transcriptional analysis identified two distinct fibroblast subsets: 33 FAPα+ THY1+ immune effector fibroblasts located in the synovial sub-34 lining, and FAPα+ THY1-destructive fibroblasts restricted to the 35 synovial lining. When adoptively transferred into the joint, FAPα+ 36 THY1-fibroblasts selectively mediate bone and cartilage damage with 37 little effect on inflammation whereas transfer of FAPα+ THY1+ 38 fibroblasts resulted in a more severe and persistent inflammatory 39 arthritis, with minimal effect on bone and cartilage. Our findings 40 describing anatomically discrete, functionally distinct fibroblast 41 subsets with non-overlapping functions have important implications 42 Croft et al Page 3 of 35 for cell based therapies aimed at modulating inflammation and tissue 43 damage. 44 45The identification and therapeutic manipulation of leucocyte subsets and 46 the cytokines they produce, has provided the basis for the spectacular 47

Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis

“…Notably, hTNFtg pathogenic SFs were capable of initiating disease when transferred to the knees of healthy mice (7), thus underlining the dominant and autonomous role of SFs in RA pathology initiation and progression. Notably, hTNFtg SFs, have been found to highly correlate with RA human Fibroblast Like Synoviocytes (FLS) not only in their gene expression profile (8) but also in their distinct roles in the joint area, with CD90 -SFs of synovial lining driving mainly bone destruction and CD90 + SFs of sublining area driving mainly inflammation (9)(10)(11).…”

Developing protein arginine methyltransferase 1 (PRMT1) inhibitor TC-E-5003 as an antitumor drug using INEI drug delivery systems

“…New drug delivery approaches are effective in order to provide a high local concentration of the anticancer drug, enhance the efficacy of chemotherapy, as well as to reduce systemic side effects. Numerous papers have been published in the field of drug delivery carriers that validate their superior anti-tumor effect (Chakravarty et al, 2015;Croft et al, 2018;Giordano et al, 2017;Lu et al, 2014;Raza et al, 2018;Werner et al, 2013). Recently, we reported on a novel biodegradable N-Butyl-2-cyanoacrylate-based injectable in situ-forming implants, formed from n-butyl-2-cyanoacrylate (NBCA) and ethyl oleate.…”

New Developments in Transcriptomic Analysis of Synovial Tissue

“…Croft et al (42) used the serum transfer induced arthritis model in combination with the deletion of fibroblast activation protein-α (FAPα) expressing cells to interrogate the role of synovial fibroblast subsets. FAPα is expressed on both lining and sublining fibroblasts in RA, therefore offering a mechanism for the global deletion of synovial fibroblasts (42)(43)(44)(45). The deletion of FAPα + cells during arthritis led to both a significant reduction in inflammation and accelerated resolution.…”