Fc Gamma Receptors as Regulators of Bone Destruction in Inflammatory Arthritis

Zuo, Yuyue; Deng, Guo-Min

doi:10.3389/fimmu.2021.688201

Cited by 23 publications

(15 citation statements)

References 166 publications

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“…Given that FcγRI is a key immune receptor expressed in a variety of immune cells ( 29 ), FcγRI might indirectly regulate bone erosion via the recruitment and activation of immune cells during RA ( 30 ). In addition, FcγRI is also expressed in preosteoclasts and osteoclasts ( 31 , 32 ). Direct activation of FcγRI in these cells increases both osteoclast differentiation and function ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

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Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice

Liu

Qu²

2022

Front. Immunol.

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Persistent arthritis pain after resolution of joint inflammation represents a huge health burden in patients with rheumatoid arthritis (RA). However, the underling mechanisms are poorly understood. We and other groups recently revealed that FcγRI, a key immune receptor, is functionally expressed in joint nociceptors. Thus, we investigated a potential role of sensory neuron expressed FcγRI in postinflammatory arthritis pain in a mouse model of collagen antibody-induced arthritis (CAIA). Here, we show that global deletion of Fcgr1 significantly attenuated mechanical hyperalgesia in the ankle and hind paw of female mice in both inflammatory and postinflammatory phases of CAIA. No obvious differences in cartilage destruction were observed after resolution of joint inflammation between genotypes. In situ hybridization (ISH) revealed that a larger proportion of dorsal root ganglion (DRG) neurons expressed Fcgr1 mRNA signal in the late phase of CAIA. Conditional deletion of Fcgr1 in primary sensory neurons produced similar analgesic effects without affecting joint swelling. Knockdown of Fcgr1 expression within DRG in the postinflammatory phase of CAIA alleviated persistent pain. Inflammation within DRG after resolution of joint inflammation in the CAIA model was evidenced by T cell and neutrophil infiltration and upregulated mRNA expression of numerous inflammatory mediators. Yet, such changes were not altered by genetic deletion of Fcgr1. We suggest that neuroinflammation within the DRG after resolution of joint inflammation might upregulate FcγRI signaling in DRG neurons. Sensory neuron expressed FcγRI thus merits exploration as a potential target for the treatment of arthritis pain that persists in RA patients in remission.

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Section: Discussionmentioning

confidence: 99%

“…In addition, FcγRI is also expressed in preosteoclasts and osteoclasts ( 31 , 32 ). Direct activation of FcγRI in these cells increases both osteoclast differentiation and function ( 31 , 32 ). Consistent with clinical studies, the present study showed obvious cartilage destruction in the postinflammatory phase of the CAIA model.…”

Section: Discussionmentioning

confidence: 99%

Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice

Liu

Qu²

2022

Front. Immunol.

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“…Bone erosion is an important feature in inflammatory arthritis, such as rheumatoid arthritis; however, it does not occur in SLE arthritis. The receptor activator of nuclear factor kappa B ligand (RANKL) induces monocytes/macrophages to separate into osteoclasts that mitigate bone erosion ( 26 ). FcγRI is a costimulatory molecule of RANK, the receptor for RANKL that activates macrophage differentiation into osteoclasts ( 14 ).…”

Section: Igg Protects Against Bone Erosion In Sle Arthritismentioning

confidence: 99%

The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus

Qiu

Deng

2022

Front. Immunol.

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Systemic lupus erythematosus (SLE), often known simply as lupus, is a severe chronic autoimmune disease that is characterized by multi-organ and tissue damage and high levels of autoantibodies in serum. We have recently investigated, using animal models, the role of organ-deposited IgG autoantibodies in the pathogenesis of organ and tissue damage in SLE. We found that intra-organ injection of serum from mice with lupus (i.e., lupus mice) into healthy mice triggered inflammation in tissue and organs but that serum from other healthy mice did not, and that the severity of inflammation was related to the dose of serum injected. Immunohistochemistry showed that a large number of IgG molecules are deposited at the site of organ and tissue damage in lupus mice, and that IgG is a major contributor to the development of tissue inflammation triggered by serum from lupus mice or patients. The development of tissue inflammation induced by IgG in serum from lupus mice requires the presence of monocytes/macrophages, but not of lymphocytes or neutrophils; tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) and interleukin 1 (IL-1) also play essential roles in the development of tissue inflammation triggered by IgG. In addition, it has been found that TNFR1 inhibitors can suppress skin injury in lupus mice and that spleen tyrosine kinase (Syk) inhibitors, which can block the signaling transduction of IgG/Fc gamma receptors (FcγRs), can prevent and treat skin injury and kidney damage in lupus mice. We have also observed that lupus IgG might protect against bone erosion. Based on these results, we conclude that IgG plays a crucial role in the development of organ and tissue damage in SLE and in protecting bone erosion and arthritis, and we suggest that the IgG/FcγR signaling pathway is an important therapeutic target in SLE.

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“…FcγRs are receptors for the constant (Fc) region of IgG and are extensively expressed on the membrane of immune cells. CD64 (FcγRI) is the only known high-affinity FcγR for IgG with a restricted isotype specificity, whereas IgG affinity of CD32 (FcγRII) and CD16 (FcγRIII) is comparatively lower ( 7 , 8 ). Activating FcγRs with immunoreceptor tyrosine-based activation motif (ITAM) in intracellular structure, CD64 and CD16 recruit spleen tyrosine kinase (Syk), which assembles into complexes at cell membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Lupus Serum-Induced Skin Inflammation in CD64-Deficient Mice

et al. 2022

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by high autoantibodies levels and multiorgan tissue damage. The current study investigated the role of CD64 in SLE patients and animal models. According to a flow cytometry study, SLE patients showed an increase in CD64 expression in circulating monocytes. There was a correlation between CD64 and SLEDAI, blood urea nitrogen levels, and anti-Sm antibodies. In skin lesions of lupus MRL/lpr mice, there was high IgG deposition and CD64 expression. In vitro, cytokines IL-10 and IFN-γ upregulated CD64 expression in monocytes/macrophages that was inhibited by glucocorticoids. In CD64-deficient mice, skin inflammation induced by lupus serum was reduced. Furthermore, activation of spleen tyrosine kinase (Syk), Akt, and extracellular signal-regulated kinase (Erk) was inhibited in CD64-deficient monocytes. The results suggest that CD64 could be a biomarker for observing SLE progression, as well as a mechanistic checkpoint in lupus pathogenesis.

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Fc Gamma Receptors as Regulators of Bone Destruction in Inflammatory Arthritis

Cited by 23 publications

References 166 publications

Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice

Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice

The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus

Amelioration of Lupus Serum-Induced Skin Inflammation in CD64-Deficient Mice

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