Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon, Tracie A.; Obstfeld, Amrom; Moore, Kathryn J.; Golenbock, Douglas T.; Tabas, Ira

doi:10.1073/pnas.0609671104

Cited by 166 publications

(211 citation statements)

References 54 publications

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“…In the rat model, inflammation begins in the gastrointestinal tract shortly after weaning and requires normal flora [55], which may provide a rich source of TLR ligands. IFN-b has recently been shown to play a crucial role in promoting macrophage survival after TLR stimulation [56]. Thus, we suggest that enhanced type I IFN production by HLA-B27-expressing macrophages could promote survival of activated macrophages via autocrine and paracrine effects, thus sustaining production of cytokines that promote T cell activation and IFN-c synthesis [57].…”

Section: Discussionmentioning

confidence: 81%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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Section: Discussionmentioning

confidence: 81%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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“…Such lipid mediators contribute to initiation and resolution of inflammation (90). In addition, SR-A is involved in combinatorial feedback inhibition of proinflammatory signaling mediated by Toll-like receptors (91). In this regard, anti-inflammatory activities of SP-A that were previously attributed to direct binding of SP-A to Toll-like receptors (92,93) may also involve indirect regulation of SR-A via SP-R210.…”

Section: Cd11cmentioning

confidence: 99%

Surfactant Protein A (SP-A)-mediated Clearance of Staphylococcus aureus Involves Binding of SP-A to the Staphylococcal Adhesin Eap and the Macrophage Receptors SP-A Receptor 210 and Scavenger Receptor Class A

Sever-Chroneos

Krupa

Davis

et al. 2011

Journal of Biological Chemistry

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There is limited knowledge about host factors that facilitate eradication of Staphylococcus aureus infection in the lung. Methicillin-resistant S. aureus has remained a major cause of hospital-and health care-associated pneumonia since its appearance over 40 years ago and has recently become a more prominent etiology in community acquired pneumonia. Colonization of nasal epithelium with S. aureus, a normal occurrence in over 20% of the population, increases the risk for the development of staphylococcal pneumonia (1). Furthermore, S. aureus co-infections are a major complication contributing to high morbidity and mortality during both pandemic and seasonal influenza virus pneumonia (2). S. aureus deploys a combination of virulence factors, including adhesins, toxins, and immunomodulatory molecules, that facilitate infection of different host tissues (3, 4).Surfactant protein A (SP-A) 3 is a crucial component of the pulmonary innate immune system in the alveolar spaces (5, 6). SP-A is the major protein constituent of pulmonary surfactant; it is involved in organization of large aggregate surfactant phospholipids lining the alveolar surface and acts as an opsonin for pathogens (7). SP-A is incorporated in the tubular myelin fraction of pulmonary surfactant that covers the alveolar lining fluid of the distal airway epithelium. The presence of pathogen-derived molecules may trigger reorganization of surfactant lipids (8 -11) and exposure of SP-A to bind pathogens at points of entry on the surfactant interface. Alveolar macrophages in the aqueous hypophase may then patrol areas of disturbance on the surfactant layer binding SP-A-opsonized bacteria. SP-A binds pathogens via a carboxyl-terminal carbohydrate recognition domain in a calcium-dependent manner. Amino-terminal collagen-like and coiled-coil do-

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“…87 IFN-b has well-recognized autocrine effects at low concentrations, [88][89][90] and thus UPR-induced IFN-b may have immunological consequences including a pro-survival effect on macrophages. 91 However, perhaps more important is the response observed when macrophages undergoing a UPR are exposed to ligands for pattern recognition receptors (e.g., Toll-like receptors or TLRs). TLR4 and TLR3 agonists such as LPS and dsRNA, that upregulate IFN-b via the TRIF (Toll-like receptor/IL-1 receptor related adaptor protein inducing IFN-b)-dependent pathway, cause robust synergistic IFN-b production in cells exhibiting ER stress.…”

Section: Evaluating the Role Of Hla-b27 In Diseasementioning

confidence: 99%

HLA-B27 Misfolding and Spondyloarthropathies

Colbert

DeLay

Layh‐Schmitt

et al. 2009

Advances in Experimental Medicine and Biology

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HLA-B27 plays a central role in the pathogenesis of many spondyloarthropathies and in particular ankylosing spondylitis. The observation that the HLA-B27 heavy chain has a tendency to misfold has raised the possibility that associated diseases may belong in a rapidly expanding category of protein misfolding disorders. The synthesis of the HLA-B27 heavy chain, assembly with β 2 m and the loading of peptide cargo, occurs in the endoplasmic reticulum (ER) before transport to the cell surface. The evidence indicates that misfolding occurs in the ER prior to β 2 m association and peptide optimization and is manifested in the formation of aberrant inter-and intra-chain disulfide bonds and accumulation of heavy chain bound to the chaperone BiP. Enhanced accumulation of misfolded heavy chains during the induction of class I expression by cytokines, can cause ER stress resulting in activation of the unfolded protein response (UPR).Effects of UPR activation on cytokine production are beginning to emerge and may provide important missing links between HLA-B27 misfolding and spondyloarthritis. In this chapter we will review what has been learned about HLA-B27 misfolding in human cells and in the transgenic rat model of spondyloarthritis-like disease, considering it in the context of other protein misfolding disorders. These studies provide a framework to support much needed translational work assessing HLA-B27 misfolding and UPR activation in patient-derived material, its consequences for disease pathogenesis and ultimately how and where to focus intervention strategies.

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Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Cited by 166 publications

References 54 publications

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Surfactant Protein A (SP-A)-mediated Clearance of Staphylococcus aureus Involves Binding of SP-A to the Staphylococcal Adhesin Eap and the Macrophage Receptors SP-A Receptor 210 and Scavenger Receptor Class A

HLA-B27 Misfolding and Spondyloarthropathies

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