Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6:579-586

Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, California 94143, USA.
Nature Immunology (Impact Factor: 20). 07/2005; 6(6):579-86. DOI: 10.1038/ni1204
Source: PubMed


DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.

  • Source
    • "Functionally, rat NK receptors may also have adapted differently to the microbial flora the two species have been exposed to. In mice lacking the adaptor molecule DAP12 associated with activating Ly49 NK receptors, the innate immune response to the intracellular bacterium Listeria monocytogenes (LM) is enhanced (58). In contrast, NK cells have a primary role in early resistance to LM in the rat (59, 60). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this review, I summarize some of the early research on NK cell biology and function that led to the discovery of a totally new receptor system for polymorphic MHC class I molecules. That NK cells both could recognize and kill tumor cells but also normal hematopoietic cells through expression of MHC class I molecules found a unifying explanation in the "missing self" hypothesis. This initiated a whole new area of leukocyte receptor research. The common underlying mechanism was that NK cells expressed receptors that were inhibited by recognition of unmodified "self" MHC-I molecules. This could explain both the killing of tumor cells with poor expression of MHC-I molecules and hybrid resistance, i.e., that F1 hybrid mice sometimes could reject parental bone marrow cells. However, a contrasting phenomenon termed allogeneic lymphocyte cytotoxicity in rats gave strong evidence that some of these receptors were activated rather than inhibited by recognition of polymorphic MHC-I. This was soon followed by molecular identification of both inhibitory and stimulatory Ly49 receptors in mice and rats and killer cell immunoglobulin-like receptors in humans that could be either inhibited or activated when recognizing their cognate MHC-I ligand. Since most of these receptors now have been molecularly characterized, their ligands and the intracellular pathways leading to activation or inhibition identified, we still lack a more complete understanding of how the repertoire of activating and inhibitory receptors is formed and how interactions between these receptors for MHC-I molecules on a single NK cell are integrated to generate a productive immune response. Although several NK receptor systems have been characterized that recognize MHC-I or MHC-like molecules, I here concentrate on the repertoires of NK receptors encoded by the natural killer cell gene complex and designed to recognize polymorphic MHC-I molecules in rodents, i.e., Ly49 (KLRA) receptors.
    Full-text · Article · Jun 2014 · Frontiers in Immunology
  • Source
    • "A rodent study showed that deletion of DAP12 induces synaptic impairments due to microglial dysfunction15. Hamerman et al.35 demonstrated that macrophage from DAP12-deficient mice increase inflammatory cytokines' responses, which suggest that DAP12-deleted microglia increase similar inflammatory response. These previous reports and our present findings based on the iMG cells from a NHD patient suggest that human NHD microglia has the potential to induce stronger and long-acting pro-inflammatory reactions compared to those of healthy human subjects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglia have been implicated in various neurological and psychiatric disorders in rodent and human postmortem studies. However, the dynamic actions of microglia in the living human brain have not been clarified due to a lack of studies dealing with in situ microglia. Herein, we present a novel technique for developing induced microglia-like (iMG) cells from human peripheral blood cells. An optimized cocktail of cytokines, GM-CSF and IL-34, converted human monocytes into iMG cells within 14 days. The iMG cells have microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. To confirm clinical utilities, we developed iMG cells from a patient of Nasu-Hakola disease (NHD), which is suggested to be directly caused by microglial dysfunction, and observed that these cells from NHD express delayed but stronger inflammatory responses compared with those from the healthy control. Altogether, the iMG-technique promises to elucidate unresolved aspects of human microglia in various brain disorders.
    Full-text · Article · May 2014 · Scientific Reports
  • Source
    • "TREM2 reduces macrophage activation and inhibits cytokine production in response to both TLR2 and TLR4 ligands zymosan and LPS [24] [25]. Conversely reduction of TREM2 expression by either RNA interference or by targeted gene deletion amplified inflammatory cytokine responses by macrophages following stimulation of multiple different TLRs including TLR2, 4, and 9 [26]. Hence, it has been speculated that TREM2 has a protective role in AD pathogenesis; its anti-inflammatory properties could reduce inflammation-induced innocent bystander neuronal damage [8] [16] [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid β (A β ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.
    Full-text · Article · Oct 2013 · International Journal of Cell Biology
Show more