Apoptotic cells induce Mer tyrosine kinase–dependent blockade of NF-κB activation in dendritic cells

Abstract

IntroductionDendritic cells (DCs) are potent mediators of T-cell activation and proinflammatory immune responses to foreign antigens and pathogens. 1,2 However, DCs also have an important role in maintaining immune homeostasis and tolerance to self-proteins. [3][4][5][6][7] These 2 opposing functions are believed in part to reflect differences in DC activation, maturation, and/or subset. Tolerogenic DCs typically exhibit an immature phenotype characterized by low cell-surface expression of MHC and costimulatory molecules and do not secrete proinflammatory cytokines. Furthermore, soluble and cellular mediators that inhibit DC activation and maturation can establish a tolerogenic phenotype. For example, binding to and phagocytosis of apoptotic cells (ACs) by immature DCs inhibits activation and maturation induced by various stimuli. 8,9 This inhibitory effect serves an important role because ACs are present in tissues under both homeostatic and inflamed conditions and provide a potential source of self-proteins to mediate autoimmunity. Defective clearance of ACs has been linked to different types of autoimmunity. 10,11 A number of receptors expressed by immature DCs such as the phosphatidylserine (PS) receptor, CD36, ␣ v ␤ 5 integrin, and complement receptor C1qR are involved in AC binding and/or ingestion. [12][13][14][15] However, the relative contribution of these receptors in mediating the immunoregulatory effect(s) of ACs on immature DCs is unclear, and the molecular basis for this inhibition has not been defined in DCs.Recently, the Axl/Mer/Tyro3 receptor tyrosine kinase (RTK) family has been implicated in homeostatic regulation of antigenpresenting cell (APC) activation. 16,17 This family, consisting of Axl, Tyro3, and MerTK, is expressed by a variety of cell types, including macrophages (Ms) and DCs. Mice lacking expression of all 3 RTKs exhibit hyperactivated Ms and DCs, which in turn drive lymphoproliferation and systemic autoimmunity. 16 Similarly, our group has shown that mice lacking MerTK expression (MerT-K KD ) develop lupuslike autoimmunity and are more prone to lipopolysaccharide (LPS)-induced endotoxic shock. [18][19][20] Autoimmunity in MerTK KD mice correlates with a reduced rate of in vivo clearance of ACs, which is consistent with findings that MerTK mediates AC phagocytosis by Ms. 19,20 A ligand for MerTK is growth arrest-specific gene 6 (GAS6), which binds to PS expressed on the inverted plasma membrane of ACs. 21 Recognition of a GAS6-PS complex facilitates binding of ACs and subsequent phagocytosis by Ms. Accordingly, MerTK has been proposed to facilitate phagocytosis of ACs and down-regulate activation in Ms. [17][18][19][20] Whether MerTK functions similarly in DCs has yet to be determined.We and others [22][23][24][25][26][27] have demonstrated a key role for the transcription factor NF-B in regulating gene expression associated with the development, activation, maturation, and APC function of DCs. The NF-B complex consists of homodimers and heterodimers of the structurally related pro...

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…Here, we show that TLR4‐specific ultrapure (up)LPS‐primed phenotypically activated BMDC, rather than worsening the severity of EAU, significantly prevent the development of EAU. We show that upLPS‐primed BMDC are endotoxin homotolerant (ET‐BMDC) and further show that they are heterotolerant to M. tuberculosis protein extract in that they are (i) susceptible to apoptosis45, 46, 47 (confirmed here) through a CD14/nuclear factor of activated T cells (NFATc)‐associated mechanism, and (ii) fail to secrete IL‐1 β on exposure to M. tuberculosis extract. As M. tuberculosis mediated C‐type lectin receptor signalling via the Syk/CARD‐9 complex,48 a major route for inflammasome activation, has been shown to be an essential mediator of IRBP‐CFA‐induced EAU,48, 49 we propose that inhibition of IL‐1 β secretion is one mechanism whereby heterotolerant LPS‐primed BMDC promote immunological tolerance.…”

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

“…The NF-kB pathway acts as a master regulator of the inflammatory response in MFs (23), and uptake of ACs was reported to interfere with NF-kB activity in various cell types (24). Notably, analysis of the NF-kB-signaling cascade revealed a block of the LPS-induced phosphorylation of NF-kB subunit p65 at serine 536 in resident MFs ingesting either ACs or PS-containing liposomes (Fig.…”

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

“…High concentrations of HSP-27 (1000 ng/mL) might induce such elevated PD-L1 levels, thereby triggering increased apoptosis in MO?iDC differentiation cultures. Uptake of apoptotic cells inhibits MO?iDC differentiation and HSP-27-mediated increased apoptosis could be a mechanism of HSP-27 inhibitory activity [40,41]. rhHSP-27 induced some apoptosis in MO?iDC differentiation culture at the concentration of 1000 ng/mL (Fig.…”