Abstract
BackgroundLeukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology. Among the infiltrating cells, monocytes comprise the largest population and are considered to play a dual role in the course of the disease. The enzyme tissue transglutaminase (TG2), produced by monocytes, plays a central role in monocyte adhesion/migration in animal models of MS. In the present study, we questioned whether TG2 expression is altered in monocytes from MS patients compared to healthy control (HC) subjects. Moreover, we determined the inflammatory status of these TG2-expressing monocytes, what inflammatory factor regulates TG2 expression, and whether TG2 can functionally contribute to their adhesion/migration processes.MethodsPrimary human monocytes from MS patients and HC subjects were collected, RNA isolated and subjected to qPCR analysis. Human THP-1 monocytes were lentivirally transduced with TG2 siRNA or control and treated with various cytokines. Subsequently, mRNA levels of inflammatory factors, adhesion properties, and activity of RhoA were analyzed in interleukin (IL)-4-treated monocytes.ResultsTG2 mRNA levels are significantly increased in monocytes derived from MS patients compared to HC subjects. In addition, correlation analyses indicated that TG2-expressing cells display a more anti-inflammatory, migratory profile in MS patients. Using THP-1 monocytes, we observed that IL-4 is a major trigger of TG2 expression in these cells. Furthermore, knockdown of TG2 expression leads to a pro-inflammatory profile and reduced adhesion/migration properties of IL-4-treated monocytes.ConclusionsTG2-expressing monocytes in MS patients have a more anti-inflammatory profile. Furthermore, TG2 mediates IL-4-induced anti-inflammatory status in THP-1 monocytes, adhesion, and cytoskeletal rearrangement in vitro. We thus propose that IL-4 upregulates TG2 expression in monocytes of MS patients, driving them into an anti-inflammatory status.
Highlights
Leukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology
transglutaminase 2 (TG2) mRNA levels were increased in MS patient-derived monocytes compared to healthy control (HC) subject-derived monocytes At first, we established that there was no significant difference in TG2 expression between untreated and drugtreated MS patients
MS patient-derived monocytes showed a decrease in IL1β mRNA and an increase in β3 integrin mRNA levels compared to HC subject-derived monocytes Subsequently, we aimed to study the inflammatory phenotype of MS patient/HC subject-derived monocytes
Summary
Leukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology. Multiple sclerosis (MS) is a chronic neurological disorder affecting mostly young adults that leads to, e.g., sensory, motor, and cognitive deficits [1] It is characterized by inflammation, demyelination, and axonal loss in the central nervous system (CNS) [2]. The pathophysiology is not well understood, MS results in leukocyte infiltration into the CNS parenchyma which requires passage of the blood-brain barrier (BBB) [3] This process is initiated by the secretion of cytokines and chemokines which induce leukocyte activation by stimulating conformational changes in the integrins, key regulators of the adhesion/migration cascade. Administration of anti-inflammatory-tuned monocytes to animals suffering from severe EAE ameliorates their clinical disease status [17,18,19]
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