IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

Chen, Zhihong; Su, Lei; Xu, Qingan; Katz, Jannet; Michalek, Suzanne M.; Fan, Mingwen; Xu, Feng; Zhang, Ping

doi:10.1074/jbc.m115.663518

Cited by 31 publications

(32 citation statements)

References 81 publications

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“…It has been reported that TLR2 modulates osteoclastogenesis and upregulates NFATc1 19 . We examined the effect of matrilin2 on NFATc1 level and activity.…”

Section: Resultsmentioning

confidence: 99%

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

Song

et al. 2017

ATVB

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Objective Extracellular matrix (ECM) proteinases are implicated in the pathogenesis of calcific aortic valve disease (CAVD). The ADAMTS5 (A Disintegrin and Metalloproteinase with Thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading ECM proteins, particularly matrilin2. We sought to determine the role of the ADAMTS5/matrilin2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with CAVD. Approach and Results Levels of ADAMTS5, matrilin2 and α-smooth muscle actin (α-SMA) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin2 and α-SMA. Treatment of normal VICs with soluble matrilin2 caused an increase in α-SMA level through Toll-like receptor 2 and 4, which was accompanied by upregulation of Runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin2. Matrilin2 activated NF-κB and nuclear factor of activated T cells complex 1 (NFATc1), and induced the interaction of these two nuclear factors. Inhibition of either NF-κB or NFATc1 suppressed matrilin2’s effect on VIC phenotype change. Knockdown of α-SMA reduced and over-expression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. Conclusions Matrilin2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NFATc1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying CAVD progression.

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“…It has been reported that TLR2 modulates osteoclastogenesis and upregulates NFATc1 19 . We examined the effect of matrilin2 on NFATc1 level and activity.…”

Section: Resultsmentioning

confidence: 99%

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

Song

et al. 2017

ATVB

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“…Murine bone marrow (BM) cells were collected from the femurs and tibias as previously described (79)(80)(81)(82). Single-cell suspensions were prepared by mechanically dispersing the BM through a 40-m cell strainer.…”

Section: Methodsmentioning

confidence: 99%

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

Zhang

et al. 2017

Infect Immun

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Porphyromonas gingivalis, a major etiologic agent of periodontitis, has been reported to induce the expansion of myeloid-derived suppressor cells (MDSC); however, little is known regarding the subpopulations of MDSC expanded by P. gingivalis infection. Flow cytometry was used to evaluate bone marrow and spleen cells from mice infected with P. gingivalis and controls for surface expression of CD11b, Ly6G, and Ly6C. To characterize the phenotype of MDSC subpopulations induced by infection, cells were sorted based on the differential expression of Ly6G and Ly6C. Moreover, since MDSC are suppressors of T cell immune activity, we determined the effect of the induced subpopulations of MDSC on the proliferative response of OVAspecific CD4 ϩ T cells. Lastly, the plasticity of MDSC to differentiate into osteoclasts was assessed by staining for tartrate-resistant acid phosphatase activity. P. gingivalis infection induced the expansion of three subpopulations of MDSC (Ly6G ϩϩ Ly6C ϩ , Ly6G ϩ Ly6C ϩϩ , and Ly6G ϩ Ly6C ϩ ); however, only CD11b ϩ Ly6G ϩ Ly6C ϩϩ -exp ressing cells exerted a significant suppressive effect on T cell proliferation. Inhibition of proliferative responses required T cell-MDSC contact and was mediated by inducible nitric oxide synthase and cationic amino acid transporter 2 via gamma interferon. Furthermore, only the CD11b ϩ Ly6G ϩ Ly6C ϩϩ subpopulation of MDSC induced by P. gingivalis infection was able to differentiate into osteoclasts. Thus, the inflammatory response induced by P. gingivalis infection promotes the expansion of immune-suppressive cells and consequently the development of regulatory inhibitors that curtail the host response. Moreover, monocytic MDSC have the plasticity to differentiate into OC, thus perhaps contributing to the OC pool in states of periodontal disease. KEYWORDS periodontitis, Porphyromonas gingivalis, MDSC Periodontitis is an infectious inflammatory process that affects the periodontium. The continuous inflammation characteristic of this disease underlies its chronic inflammatory nature, ultimately destroying the supportive tissues of teeth (1, 2). Current thought suggests that the development of periodontitis is associated with a shift from a balanced microbial community to an imbalanced one, with the ability to undermine the host response and allowing the persistence of pathogens in the inflammatory milieu (3,4). Within the oral microflora, Porphyromonas gingivalis is considered a key pathogen able to exert an influence on the microbial environment and, consequently, in concert with other periodontal microorganisms, initiate and promote periodontitis (5, 6). P. gingivalis has a number of virulence factors by which it can escape or dampen host immunity, alter cytokine production, and affect the cell signaling mechanisms (7-10). Interestingly, studies in mice infected with P. gingivalis

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“…Once activated, most TLRs signal through MyD88 to induce cytokine production (24). This signaling can result in arthritis and osteoclastogenesis in murine models of bacterium-induced focal complications (25)(26)(27). Host cells reportedly recognize Brucella through TLR2, TLR4, TLR6, and TLR9 (28)(29)(30)(31)(32).…”

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confidence: 99%

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

et al. 2017

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Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis, and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report C57BL/6 WT mice infected via the footpad with 10 3 to 10 6 CFU of Brucella spp. display neutrophil and monocyte infiltration of the joint space and surrounding musculoskeletal tissue. Joint inflammation is detectable as early as 1 day postinfection and peaks 1 to 2 weeks later, after which WT mice are able to slowly resolve inflammation. B and T cells were dispensable for the onset of swelling but required for resolution of joint inflammation and infection. At early time points, MyD88 Ϫ/Ϫ mice display decreased joint inflammation, swelling, and proinflammatory cytokine levels relative to WT mice. Subsequently, swelling of MyD88 Ϫ/Ϫ joints surpassed WT joint swelling, and resolution of joint inflammation was prolonged. Joint bacterial loads in MyD88 Ϫ/Ϫ mice were significantly greater than those in WT mice by day 3 postinfection and at all time points thereafter. In addition, MyD88 Ϫ/Ϫ joint inflammatory cytokine levels on day 3 and beyond were similar to WT levels. Collectively these data demonstrate MyD88 signaling mediates early inflammatory responses in the joint but also contributes to subsequent clearance of Brucella and resolution of inflammation. This work also establishes a mouse model for studying Brucellainduced arthritis, musculoskeletal complications, and systemic responses, which will lead to a better understanding of focal complications of brucellosis.KEYWORDS arthritis, osteomyelitis, Brucella, brucellosis, MyD88, musculoskeletal B rucella spp. infect over 500,000 individuals each year, making brucellosis one of the most common global zoonoses (1). The most prevalent species that infect humans are Brucella melitensis, Brucella abortus, and Brucella suis (2). Transmission to humans typically occurs through the consumption of unpasteurized dairy products or via aerosol following contact with contaminated meat products (3, 4). Although vaccination of livestock has reduced disease incidence, no licensed human vaccine is available, and brucellosis has recently been designated a neglected zoonotic disease by the World Health Organization (5, 6). Osteoarticular and musculoskeletal inflammation are the most common focal complications of human brucellosis and occur in 40 to 80% of Brucella-infected patients (7,8). This arthritis is thought to arise from the hematogenous spread of Brucella to the joints, as viable brucellae can be found within the synovial fluid of infected patients (9, 10). Arthritis can manifest as peripheral arthritis, sacroiliitis, and spondylitis, which are most common in children, young adults and older adults, respectively (7,8,11,12). Inflammation of the joint synovium is pre...

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IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

Cited by 31 publications

References 81 publications

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

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