Innate Immunity Pathways in Autoimmune Diseases

Editorial

04 June 2019

Editorial: Innate Immunity Pathways in Autoimmune Diseases

Moncef Zouali

and

Antonio La Cava

6,577 views

9 citations

Editors

Moncef Zouali

Institut National de la Santé et de la Recherche Médicale (INSERM)

Antonio La Cava

University of California, Los Angeles

Impact

Review

16 May 2018

The Interplay Between Innate-Like B Cells and Other Cell Types in Autoimmunity

Gregory J. Tsay

and

Moncef Zouali

10,941 views

39 citations

DICER1 functions at the crossroads of inflammation, senescence and aging. Examples of microRNAs involved in both rheumatoid arthritis (RA) and inflammation (miR-155 and -146a), RA and senescence (miR-34a) or RA and stress (miR-124a) are shown. The model illustrates how an initial trigger (e.g., a viral infection) might initiate a vicious circle (see text).

Mini Review

24 July 2018

DICER1: A Key Player in Rheumatoid Arthritis, at the Crossroads of Cellular Stress, Innate Immunity, and Chronic Inflammation in Aging

Aurore De Cauwer

, 3 more and

Philippe Georgel

7,167 views

17 citations

Survival rate is much longer in semaphorin3A (sema3A)-treated mice and shorter in control-treated mice.

Original Research

04 April 2018

Semaphorin3A: A Potential Therapeutic Tool for Lupus Nephritis

Jacob Bejar

, 5 more and

Zahava Vadasz

2,905 views

18 citations

Original Research

19 March 2018

Astrocytic Interleukin-15 Reduces Pathology of Neuromyelitis Optica in Mice

Zhiguo Li

, 5 more and

Minshu Li

3,037 views

14 citations

Perspective

06 July 2018

Potential Chronotherapeutic Optimization of Antimalarials in Systemic Lupus Erythematosus: Is Toll-Like Receptor 9 Expression Dependent on the Circadian Cycle in Humans?

Erika Aurora Martínez-García

, 5 more and

Mónica Vázquez-Del Mercado

4,834 views

6 citations

Original Research

12 March 2018

Computational Insight Into the Structural Organization of Full-Length Toll-Like Receptor 4 Dimer in a Model Phospholipid Bilayer

Mahesh Chandra Patra

, 2 more and

Sangdun Choi

Views of TAK-242 binding cavities of different toll/interleukin-1 receptor (TIR) dimer models. (A) TAK-242 binding pocket of TIR dimer in simulation 1. (B) TAK-242 binding pocket of TIR dimer in simulation 2. (C) TAK-242 binding pocket of isolated TIR dimer. (D) Interaction of TAK-242 with the TIR domain dimer residues. (E) Distance between the TAK-242 cyclohexane ring and the –SH2 group of C747 of both TIR monomers.

Toll-like receptors (TLRs) are a unique category of pattern recognition receptors that recognize distinct pathogenic components, often utilizing the same set of downstream adaptors. Specific molecular features of extracellular, transmembrane (TM), and cytoplasmic domains of TLRs are crucial for coordinating the complex, innate immune signaling pathway. Here, we constructed a full-length structural model of TLR4—a widely studied member of the interleukin-1 receptor/TLR superfamily—using homology modeling, protein–protein docking, and molecular dynamics simulations to understand the differential domain organization of TLR4 in a membrane-aqueous environment. Results showed that each functional domain of the membrane-bound TLR4 displayed several structural transitions that are biophysically essential for plasma membrane integration. Specifically, the extracellular and cytoplasmic domains were partially immersed in the upper and lower leaflets of the membrane bilayer. Meanwhile, TM domains tilted considerably to overcome the hydrophobic mismatch with the bilayer core. Our analysis indicates an alternate dimerization or a potential oligomerization interface of TLR4-TM. Moreover, the helical properties of an isolated TM dimer partly agree with that of the full-length receptor. Furthermore, membrane-absorbed or solvent-exposed surfaces of the toll/interleukin-1 receptor domain are consistent with previous X-ray crystallography and biochemical studies. Collectively, we provided a complete structural model of membrane-bound TLR4 that strengthens our current understanding of the complex mechanism of receptor activation and adaptor recruitment in the innate immune signaling pathway.

25,017 views

24 citations

Original Research

26 February 2018

The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells

Vaclav Janovec

, 11 more and

Ivan Hirsch

7,161 views

23 citations

Original Research

29 January 2018

TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles

Mojca Frank-Bertoncelj

, 5 more and

Steffen Gay

Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma).

14,670 views

18 citations

Analysis of the correlations and structure of the interferon (IFN)-responding genes (IRGs) networks. (A) Analyses of the correlations among IRG in the different groups studied. Correlation matrices were plotted in 2 × 2 correlograms. Correlation coefficients were depicted in white. Color of the tiles is proportional to the strength of the correlation (color scale is represented at the bottom of each grap). (B) Network analyses of the IRGs in the groups studied. Each node corresponds to an IRG, and the lines illustrate the strength (width) and sign (green, positive; red, negative) of the correlations between each pair of variables. The interferon (IFN) network in healthy control (HC) is characterized by a group of three IRGs closely correlated [IFN-induced protein 44 like (IFI44L), MX dynamin-like GTPase 1, and IFN alpha inducible protein 6 (IFI6)], almost not related to IFI44L. Stronger correlations were observed in very early rheumatoid arthritis (VERA) and rheumatoid arthritis (RA) established groups compared to HC, and a more complex, intricate network was observed in biological disease-modifying antirheumatic drug (bDMARD) patients, with a closer location of all IRGs and a strong correlation between IFN-induced protein 44 (IFI44) and IFI44L. Similarly, a correlation between IFI6 and IFI44 is differentially expressed in established RA, compared to VERA or HC. Additional information on the network structure and its overall activation was summarized in the table at the bottom of the figure.

Original Research

16 January 2018

Heterogeneity of the Type I Interferon Signature in Rheumatoid Arthritis: A Potential Limitation for Its Use As a Clinical Biomarker

Javier Rodríguez-Carrio

, 3 more and

Ana Suárez

5,039 views

41 citations

Original Research

25 September 2017

Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils

Yebin Zhou

, 18 more and

Gary P. Sims

Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA), and elevated levels of protein citrullination can be found in the joints of patients with RA. Calcium-dependent peptidyl-arginine deiminases (PAD) are the enzymes responsible for citrullination. PAD2 and PAD4 are enriched in neutrophils and likely drive citrullination under inflammatory conditions. PADs may be released during NETosis or cell death, but the mechanisms responsible for PAD activity under physiological conditions have not been fully elucidated. To understand how PADs citrullinate extracellular proteins, we investigated the cellular localization and activity of PAD2 and PAD4, and we report that viable neutrophils from healthy donors have active PAD4 exposed on their surface and spontaneously secrete PAD2. Neutrophil activation by some stimulatory agents increased the levels of immunoreactive PAD4 on the cell surface, and some stimuli reduced PAD2 secretion. Our data indicate that live neutrophils have the inherent capacity to express active extracellular PADs. These novel pathways are distinguished from intracellular PAD activation during NETosis and calcium influx-mediated hypercitrullination. Our study implies that extracellular PADs may have a physiological role under non-pathogenic conditions as well as a pathological role in RA.