Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions.

Xianmei Liu,Xueyu Geng,Lanping Amy Sung,Zhu Zeng,Weijuan Yao,Xifu Wang,Jing Zhou,Xue Xia,Jinhua Long

doi:10.3389/fimmu.2020.587441

Abstract

Dendritic cells (DCs) are the most potent antigen-presenting cells. Upon maturation, DCs express costimulatory molecules and migrate to the lymph nodes to present antigens to T cells. The actin cytoskeleton plays key roles in multiple aspects of DC functions. However, little is known about the mechanisms and identities of actin-binding proteins that control DC maturation and maturation-associated functional changes. Tropomodulin1 (Tmod1), an actin-capping protein, controls actin depolymerization and nucleation. We found that Tmod1 was expressed in bone marrow-derived immature DCs and was significantly upregulated upon lipopolysaccharide (LPS)-induced DC maturation. By characterizing LPS-induced mature DCs (mDCs) from Tmod1 knockout mice, we found that compared with Tmod1+/+ mDCs, Tmod1-deficient mDCs exhibited lower surface expression of costimulatory molecules and chemokine receptors and reduced secretion of inflammatory cytokines, suggesting that Tmod1 deficiency retarded DC maturation. Tmod1-deficient mDCs also showed impaired random and chemotactic migration, deteriorated T-cell stimulatory ability, and reduced F-actin content and cell stiffness. Furthermore, Tmod1-deficient mDCs secreted high levels of IFN-β and IL-10 and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model. Mechanistically, Tmod1 deficiency affected TLR4 signaling transduction, resulting in the decreased activity of MyD88-dependent NFκB and MAPK pathways but the increased activity of the TRIF/IRF3 pathway. Rescue with exogenous Tmod1 reversed the effect of Tmod1 deficiency on TLR4 signaling. Therefore, Tmod1 is critical in regulating DC maturation and immune functions by regulating TLR4 signaling and the actin cytoskeleton. Tmod1 may be a potential target for modulating DC functions, a strategy that would be beneficial for immunotherapy for several diseases.

Highlights

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and play critical roles in initiating and exaggerating innate and adaptive immune responses [1, 2]
We demonstrated that Tmod1 is expressed in bone marrow-derived dendritic cells (BMDCs) and is upregulated upon lipopolysaccharide (LPS)-induced DC maturation
Using BMDCs from TOT/Tmod1-/- mice, that were obtained by crossing cardiomyocyte-specific Tmod1 overexpressing transgenic (TOT) mice with Tmod1+/- mice [37, 38], we showed that Tmod1 deficiency retarded DC maturation by downregulating the expression of costimulatory molecules and inflammatory cytokines, and impaired their migration and T-cell stimulatory abilities by altering their actin cytoskeleton and cell mechanics

Summary

Introduction

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and play critical roles in initiating and exaggerating innate and adaptive immune responses [1, 2]. Upon capturing antigens through pattern recognition receptors such as Toll-like receptors (TLRs), imDCs gradually develop into mature DCs (mDCs) through the activation of MyD88- and TRIF-dependent signaling pathways [8, 9]. This occurs in concert with the translocation of MHC-II from endosomal compartments to the plasma membrane, and the upregulation of costimulatory molecules, chemokine receptors, and cytokines [10,11,12,13]. MDCs migrate to the lymphoid organs and present the antigenic peptides to naïve T cells to mediate immune responses [14, 15]. A considerable amount of information about the biological behaviors of DCs is available, the molecular mechanisms underlying their differentiation, maturation, and immune functions of DCs remain elusive

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Conclusion