CELL-SPECIFIC REGULATION OF THE HTRA1–MIF AXIS DURING MULTIPLE SCLEROSIS PROGRESSION

High temperature requirement serine protease A1 (HTRA1) and macrophage migration inhibitory factor (MIF) are both implicated in neuroinflammation and tissue remodeling, yet their functional interaction in multiple sclerosis (MS) remains poorly understood. We have previously demonstrated that HTRA1 levels are increased in cerebrospinal fluid (CSF) from MS patients and correlate with disease severity. In contrast, MIF levels are reduced in relapsing–remitting MS (RRMS) and increased in progressive disease. Importantly, MIF binds to and inhibits the enzymatic activity of HTRA1, providing a rationale for examining the balance between these proteins in MS.
We investigated the HTRA1/MIF ratio in CSF from healthy controls, treatment-naïve RRMS patients, and secondary progressive MS (SPMS) patients before and after disease-modifying therapy. In RRMS, the HTRA1/MIF ratio was significantly increased compared to controls, reflecting elevated HTRA1 levels combined with reduced MIF. In contrast, the ratio was decreased in SPMS, driven by increased levels of both proteins. Treatment with dimethyl fumarate normalized the ratio in RRMS, whereas mitoxantrone treatment had no consistent effect in SPMS.
Receiver operating characteristic analyses showed that the HTRA1/MIF ratio robustly discriminated treatment-naïve RRMS from SPMS with high sensitivity and specificity, outperforming either biomarker alone. The ratio did not correlate with relapse status or short-term disease activity, suggesting that it reflects disease stage–specific pathology rather than acute inflammation.
Together, these findings identify the HTRA1–MIF axis as a stage-dependent regulatory mechanism in MS. The HTRA1/MIF ratio may therefore serve as a mechanistically informed biomarker for MS progression and patient stratification.