Mannose Receptor C type 2 influences autoimmune neuroinflammation and blood-brain barrier integrity

Relapses in Multiple Sclerosis (MS) are driven by pathogenic immune cells breaching the disrupted blood–brain barrier (BBB), leading to tissue damage and eventual disease progression ^1–3 . Among the most effective therapies are those that block immune cell infiltration across the BBB, a multistep process involving activation, adhesion, rolling, transendothelial migration, and extracellular matrix (ECM) degradation. Current treatments broadly suppress the immune system and can cause adverse side effects ^4,5 , highlighting the need for targeted approaches. Here, we identified a previously unrecognized role of ECM remodeling pathways and Mannose Receptor C-type 2 (MRC2) in invasive T lymphocytes as a potential therapeutic target. Typically low under physiological conditions, MRC2 was upregulated on T lymphocytes upon inflammatory stimulation in vitro, enriched in the periphery of MS patients during relapse and progressive disease, and present in cerebrospinal fluid and active brain lesions co-localized with Col IV, the major ECM component of the BBB. Genetic deletion of MRC2 impaired T lymphocyte-mediated Col IV degradation, adhesion, and transendothelial migration, and leading to reduced neuroinflammation in a sex-dependent manner in an MS-like mouse model. These findings suggest MRC2 as a key regulator of T lymphocyte infiltration into the CNS and a promising target for MS therapy.