TLR7/9-mediated monocytosis and maturation of Gr-1(hi) inflammatory monocytes towards Gr-1(lo) resting monocytes implicated in murine lupus.
ABSTRACT Circulating monocytes are divided into two major, phenotypically and functionally distinct subsets: Gr-1(hi) "inflammatory" and Gr-1(lo) "resting" monocytes. One of the unique cellular abnormalities in lupus-prone mice is monocytosis, which is characterized by a selective expansion of Gr-1(lo) monocytes and dependent on the expression of stimulatory IgG Fc receptors (FcγR). We speculated that IgG immune complexes containing nuclear antigens could stimulate Gr-1(hi) monocytes through interaction with FcγRs and then TLR7 and TLR9, thereby promoting the maturation towards Gr-1(lo) monocytes. In the present study, we assessed this hypothesis by analyzing effects of TLR9 or TLR7 agonist on monocytes in vivo. The analysis of various surface markers differentially expressed on both subsets of monocytes in combination with selective depletion of either subset revealed that within 48 h after injection of the TLR9 agonist CpG, approximately one third of Gr-1(hi) monocytes became phenotypically identical to Gr-1(lo) monocytes. In addition, we observed approximately two-fold increases in the total monocyte population 8-24 h after injection of CpG. Moreover, the activation of TLR9 resulted in an increased expression of stimulatory FcγRIV relative to inhibitory FcγRIIB on monocytes, thereby enhancing their responsiveness to IgG immune complexes. Essentially identical results were obtained after stimulation of TLR7 with a synthetic agonist (1V136). Our results indicate that the activation of TLR7 and TLR9 not only induced the maturation of a fraction of Gr-1(hi) monocytes towards Gr-1(lo) monocytes but also promoted the overall generation of monocytes, thereby supporting the critical role of TLR7 and TLR9 for the development of monocytosis in lupus-prone mice.
- SourceAvailable from: Leonard H Evans[Show abstract] [Hide abstract]
ABSTRACT: The envelope glycoprotein, gp70, of endogenous retroviruses represents one of the major nephritogenic autoantigens implicated in murine systemic lupus erythematosus. Among different endogenous retroviruses (ecotropic, xenotropic and polytropic), lupus-prone mice express remarkably high levels of modified polytropic (mPT) retroviruses, which are controlled by the Sgp3 (serum gp70 production) locus. To define the contribution of the Sgp3 locus derived from lupus-prone mice to the expression of the specific mPT proviruses, the genetic origin of different mPT viruses expressed in livers and thymi of wild-type and Sgp3 congenic C57BL/6 mice was determined through clonal analysis of their transcripts. Among 13 mPT proviruses present in the C57BL/6 genome, only 3 proviruses (Mpmv6, Mpmv10 and Mpmv13) were selectively but differentially expressed in livers and thymi. This was likely a result of co-regulated expression with host genes because of their integration in the same transcriptional direction. In contrast, Sgp3 induced the steady-state expression of an additional select group of mPT proviruses and, after stimulation of TLR7, the highly upregulated expression of a potentially replication-competent mPT virus Mpmv4. These results indicated that the expression of distinct subpopulations of mPT retroviruses was regulated by Sgp3- and TLR7-dependent mechanisms. The induction of potentially replication-competent mPT viruses and the upregulation of one such virus after stimulation with TLR7 in Sgp3 congenic mice further highlight the implication of Sgp3 in autoimmune responses against nephritogenic serum gp70 through the activation of TLR7.Journal of Autoimmunity 04/2012; 38(4):361-8. · 7.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Immunoglobulin G (IgG) antibodies confer protection against pathogenic microorganisms, serve as therapeutics in tumor therapy, and are involved in destruction of healthy tissues during autoimmune diseases. Understanding the molecular pathways and effector cell types involved in antibody-mediated effector functions is a prerequisite to modulate these activities. In this study we used two independent model systems to identify innate immune effector cells required for IgG activity in vivo. We first defined the precise repertoire of receptors for the IgG Fc fragment (FcγR) on innate immune effector cells in the blood and on tissue-resident macrophage populations. Despite expression of relevant activating FcγRs on various phagocyte populations, our data indicate that the majority of these cell types are dispensable for IgG activity in vivo. In contrast, IgG-dependent effector functions were selectively impaired in animals lacking the CX(3)CR1(hi)Ly6C(lo)CD11c(int) monocyte subset, which expressed the full set of FcγRs required for IgG activity.Immunity 12/2011; 35(6):932-44. · 19.75 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Autoimmune and autoinflammatory diseases are two distinct disease entities that can present in the neonate. Autoimmune diseases of the newborn primarily include neonatal lupus and neonatal anti-phospholipid syndrome, but other diseases have been reported as well. The pathogenic mechanisms behind autoimmune diseases of the newborns are unknown, but an association with antibodies to Ro and La is present in most cases. The extent to which these antibodies play a pathogenic role is unknown. Because the phenotype of clinical neonatal lupus is variable in many mothers who possess the antibodies, other mechanisms may be necessary to confer disease. The primary theories include apoptosis of cardiac cells, maternal microchimerism, cross-reactivity of the autoantibodies with cardiac tissue, T cell dysregulation and inhibitory receptors, and a genetic predisposition. The autoinflammatory diseases are unrelated to neonatal autoimmune diseases and include the cryopyrin-associated periodic syndromes (CAPS). These diseases include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease (NOMID). All of these diseases share a defect in a common gene - the CIAS1 or NALP3 gene on chromosome 1. The diseases vary in severity and involvement of different physiologic systems, with FCAS being the mildest form and NOMID being the most severe form with involvement of the neurologic and hematologic systems. Aberrant functioning of the inflammasome may play a role in the pathogenesis of autoinflammatory diseases.Journal of Autoimmunity 02/2013; · 7.02 Impact Factor