Phosphorylated ERM Is Responsible for Increased T Cell Polarization, Adhesion, and Migration in Patients with Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disease characterized by autoantibody production and abnormal T cells that infiltrate tissues through not well-known mechanisms. We report that SLE T lymphocytes display increased levels of CD44, ezrin, radixin, and moesin (ERM) phosphorylation, stronger actin polymerization, higher polar cap formation, and enhanced adhesion and chemotactic migration compared with T cells from patients with rheumatoid arthritis and normal individuals. Silencing of CD44 by CD44 small interfering RNA in SLE T cells inhibited significantly their ability to adhere and migrate as did treatment with Rho kinase and actin polymerization inhibitors. Forced expression of T567D-ezrin, a phosphorylation-mimic form, enhanced remarkably the adhesion and migration rate of normal T cells. Anti-CD3/TCR autoantibodies present in SLE sera caused increased ERM phosphorylation, adhesion, and migration in normal T cells. pERM and CD44 are highly expressed in T cells infiltrating in the kidneys of patients with lupus nephritis. These data prove that increased ERM phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients.

Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

“…Rho-associated kinase (ROCK)2 was shown recently to be implicated in the regulation of autoimmunity in mice and humans (13)(14)(15). Previous findings demonstrated that oral administration of a selective ROCK2 inhibitor (KD025) in healthy subjects decreases IL-17 and IL-21 secretion induced by ex vivo stimulation (15 immunosuppressive T cell subsets via concurrent regulation of STAT3/STAT5 phosphorylation (16)(17)(18).…”

Ezrin is a negative regulator of death receptor-induced apoptosis

“…For example, three different roles have been reported for the involvement of ezrin-moesin in immunological synapse (IS) formation: ERM was found to be essential for the assembly of IS and the recruitment of ZAP70 in one group of studies (Roumier et al, 2001;Ilani et al, 2007); ezrin was reported to be completely dispensable for IS formation in another study (Shaffer et al, 2009); and in yet a third proposal, ezrin was also declared to negatively regulate IS formation (Faure et al, 2004). Similarly, opposite effects of ERM have been documented for T-lymphocyte movement; T-cell migration could be enhanced by either ERM phosphorylation (Li et al, 2007) or ERM dephosphorylation (Brown et al, 2003). The negative effect of ezrin in Fas-induced apoptosis presented in this study, in contrast to the previously reported positive role for ezrin, highlights another controversy that is centered on the membrane events involving ERM.…”

Novel molecular targets in the treatment of systemic lupus erythematosus

“…The importance of the former findings was highlighted by the demonstration that in kidney biopsies from patients with lupus glomerulonephritis, infiltrating T cells expressed CD44 and pERM. In contrast, biopsies from allografts undergoing rejection displayed CD44+ T cells, but lacked pERM expression [14].…”

“…Hence, treatment of SLE T cells with Y27632, a specific inhibitor of Rho kinase (the enzyme that phosphorylates ERM), disrupts the formation of polar caps and hampers the increased adhesion capacity characteristic of SLE T cells. Addition of cytochalasin D (an actin polymerization inhibitor) or CD44 knockdown (by RNA interference) have shown comparable effects [14]. The importance of the former findings was highlighted by the demonstration that in kidney biopsies from patients with lupus glomerulonephritis, infiltrating T cells expressed CD44 and pERM.…”

“…Accordingly, the altered lipid raft composition outlined before is associated with an increase in the speed of actin polymerization that follows CD3-mediated stimulation (Krishnan et al, unpublished). Further, SLE T cells display an increased ability to adhere and migrate in response to chemotactic factors than T cells obtained from healthy individuals or from patients with rheumatoid arthritis [14]. CD44 is a surface molecule that has been shown to participate in T cell adhesion and migration.…”