Osteoimmunology : Interplay Between the Immune System and Bone Metabolism

C.Walsh, Matthew,Kim, Nacksung,Kadono, Yuho,Rho, Jaerang,Lee, Soo Young,Lorenzo, Joseph,Choi, Yongwon 충남대학교 형질전환복제돼지연구센터 2007 논문집 Vol. No.10

Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. The immune system is spawned in the bone marrow reservoir, and investigators now recognize that important niches also exist there for memory lymphocytes. At the same time, various factors produced during immune responses are capable of profoundly affecting regulation of bone. Mechanisms have evolved to prevent excessive interference by thc immune system with bone homeostasis, yet pathologic bone loss is a common sequela associated with autoimmunity and cancer. There are also developmental links, or parallels, between bone and the immune system. Cells that regulate bone turnover share a common precursor with inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analo￢gous to lymphocyte costimulation. Efforts are currently under way to further characterize how these two organ systems overlap and to develop therapeutic strategies that benefit from this understanding.

IL-18 Synergizes with IL-7 To Drive Slow Proliferation of Naive CD8 T Cells by Costimulating Self-Peptide–Mediated TCR Signals

Walsh, Matthew C.,Pearce, Erika L.,Cejas, Pedro J.,Lee, JangEun,Wang, Li-San,Choi, Yongwon American Association of Immunologists 2014 Journal of Immunology Vol. No.

<P>Naive T cell populations are maintained in the periphery at relatively constant levels via mechanisms that control expansion and contraction and are associated with competition for homeostatic cytokines. It has been shown that in a lymphopenic environment naive T cells undergo expansion due, at least in part, to additional availability of IL-7. We have previously found that T cell–intrinsic deletion of TNFR-associated factor (TRAF) 6 (TRAF6ΔT) in mice results in diminished peripheral CD8 T cell numbers. In this study, we report that whereas naive TRAF6ΔT CD8 T cells exhibit normal survival when transferred into a normal T cell pool, proliferation of naive TRAF6ΔT CD8 T cells under lymphopenic conditions is defective. We identified IL-18 as a TRAF6–activating factor capable of enhancing lymphopenia-induced proliferation (LIP) in vivo, and that IL-18 synergizes with high-dose IL-7 in a TRAF6-dependent manner to induce slow, LIP/homeostatic-like proliferation of naive CD8 T cells in vitro. IL-7 and IL-18 act synergistically to upregulate expression of IL-18R genes, thereby enhancing IL-18 activity. In this context, IL-18R signaling increases PI3K activation and was found to sensitize naive CD8 T cells to a model noncognate self-peptide ligand in a way that conventional costimulation via CD28 could not. We propose that synergistic sensitization by IL-7 and IL-18 to self-peptide ligand may represent a novel costimulatory pathway for LIP.</P>

Dendritic Cell Expression of the Signaling Molecule TRAF6 Is Critical for Gut Microbiota-Dependent Immune Tolerance

Han, D.,Walsh, Matthew C.,Cejas, Pedro J.,Dang, Nicholas N.,Kim, Youngmi F.,Kim, J.,Charrier-Hisamuddin, L.,Chau, L.,Zhang, Q.,Bittinger, K.,Bushman, Frederic D.,Turka, Laurence A.,Shen, H.,Reizis, B. Cell Press 2013 Immunity Vol.38 No.6

The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.

Regulator of Fatty Acid Metabolism, Acetyl Coenzyme A Carboxylase 1, Controls T Cell Immunity

Lee, JangEun,Walsh, Matthew C.,Hoehn, Kyle L.,James, David E.,Wherry, E. John,Choi, Yongwon American Association of Immunologists 2014 Journal of Immunology Vol. No.

<P>Fatty acids (FAs) are essential constituents of cell membranes, signaling molecules, and bioenergetic substrates. Because CD8<SUP>+</SUP> T cells undergo both functional and metabolic changes during activation and differentiation, dynamic changes in FA metabolism also occur. However, the contributions of de novo lipogenesis to acquisition and maintenance of CD8<SUP>+</SUP> T cell function are unclear. In this article, we demonstrate the role of FA synthesis in CD8<SUP>+</SUP> T cell immunity. T cell–specific deletion of acetyl coenzyme A carboxylase 1 (ACC1), an enzyme that catalyzes conversion of acetyl coenzyme A to malonyl coenzyme A, a carbon donor for long-chain FA synthesis, resulted in impaired peripheral persistence and homeostatic proliferation of CD8<SUP>+</SUP> T cells in naive mice. Loss of ACC1 did not compromise effector CD8<SUP>+</SUP> T cell differentiation upon listeria infection but did result in a severe defect in Ag-specific CD8<SUP>+</SUP> T cell accumulation because of increased death of proliferating cells. Furthermore, in vitro mitogenic stimulation demonstrated that defective blasting and survival of ACC1-deficient CD8<SUP>+</SUP> T cells could be rescued by provision of exogenous FA. These results suggest an essential role for ACC1-mediated de novo lipogenesis as a regulator of CD8<SUP>+</SUP> T cell expansion, and may provide insights for therapeutic targets for interventions in autoimmune diseases, cancer, and chronic infections.</P>

Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation

Hyunsoo Kim,Noriko Takegahara,Matthew C. Walsh,Jun Ueda,Yoshitaka Fujihara,Masahito Ikawa,Yongwon Choi 생화학분자생물학회 2020 BMB Reports Vol.53 No.9

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-B ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis.

The purinergic receptor P2X5 contributes to bone loss in experimental periodontitis

( Hyunsoo Kim ),( Tetsuhiro Kajikawa ),( Matthew C. Walsh ),( Noriko Takegahara ),( Yun Hee Jeong ),( George Hajishengallis ),( Yongwon Choi ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.9

Purinergic receptor signaling is increasingly recognized as an important regulator of inflammation. The P2X family purinergic receptors P2X5 and P2X7 have both been implicated in bone biology, and it has been suggested recently that P2X5 may be a significant regulator of inflammatory bone loss. However, a role for P2X5 in periodontitis is unknown. The present study aimed to evaluate the functional role of P2X5 in ligatureinduced periodontitis in mice. Five days after placement of ligature, analysis of alveolar bone revealed decreased bone loss in P2rx5^-/- mice compared to P2rx7^-/- and WT control mice. Gene expression analysis of the gingival tissue of ligated mice showed that IL1b, IL6, IL17a and Tnfsf11 expression levels were significantly reduced in P2rx5^-/- compared to WT mice. These results suggest the P2X5 receptor may regulate bone loss related to periodontitis and it may thus be a novel therapeutic target in this oral disease. [BMB Reports 2018; 51(9): 468-473]

THE LICK AGN MONITORING PROJECT: RECALIBRATING SINGLE-EPOCH VIRIAL BLACK HOLE MASS ESTIMATES

Park, Daeseong,Woo, Jong-Hak,Treu, Tommaso,Barth, Aaron J.,Bentz, Misty C.,Bennert, Vardha N.,Canalizo, Gabriela,Filippenko, Alexei V.,Gates, Elinor,Greene, Jenny E.,Malkan, Matthew A.,Walsh, Jonelle IOP Publishing 2012 The Astrophysical journal Vol.747 No.1

<P>We investigate the calibration and uncertainties of black hole (BH) mass estimates based on the single-epoch (SE) method, using homogeneous and high-quality multi-epoch spectra obtained by the Lick Active Galactic Nucleus (AGN) Monitoring Project for nine local Seyfert 1 galaxies with BH masses <10(8) M-circle dot. By decomposing the spectra into their AGNs and stellar components, we study the variability of the SE H beta line width (full width at half-maximum intensity, FWHMH beta or dispersion, sigma(H beta)) and of the AGN continuum luminosity at 5100 angstrom (L-5100). From the distribution of the 'virial products' (proportional to FWHMH beta 2 L-5100(0.5) or sigma(2)(H beta) L-5100(0.5)) measured from SE spectra, we estimate the uncertainty due to the combined variability as similar to 0.05 dex (12%). This is subdominant with respect to the total uncertainty in SE mass estimates, which is dominated by uncertainties in the size-luminosity relation and virial coefficient, and is estimated to be similar to 0.46 dex (factor of similar to 3). By comparing the H beta line profile of the SE, mean, and root-mean-square (rms) spectra, we find that the H beta line is broader in the mean (and SE) spectra than in the rms spectra by similar to 0.1 dex (25%) for our sample with FWHMH beta < 3000 km s(-1). This result is at variance with larger mass BHs where the difference is typically found to be much less than 0.1 dex. To correct for this systematic difference of the H beta line profile, we introduce a line-width dependent virial factor, resulting in a recalibration of SE BH mass estimators for low-mass AGNs.</P>

Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

Yu, Jiyeon,Yun, Hyeongseok,Shin, Bongjin,Kim, Yongjin,Park, Eui-Soon,Choi, Seunga,Yu, Jungeun,Amarasekara, Dulshara Sachini,Kim, Sumi,Inoue, Jun-ichiro,Walsh, Matthew C.,Choi, Yongwon,Takami, Masamich American Society for Biochemistry and Molecular Bi 2016 The Journal of biological chemistry Vol.291 No.39

<P>The signaling pathway downstream of stimulation of receptor activator of nuclear factor B (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANK(cyto)) to trigger downstream osteoclastogenic signaling cascades. RANK(cyto) harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANK(cyto) mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANK(cyto) mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANK(cyto) enhances downstream NF-B, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.</P>