Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis

Abstract

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.MethodsBone marrow-derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10 –/–, and Cxcr3 –/– mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.ResultsCXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression. In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10 –/– and Cxcr3 –/– mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.ConclusionThese findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1353-6) contains supplementary material, which is available to authorized users.

EnteropathogenicEscherichia coli(EPEC) Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations and Increased Intestinal Permeability in a Murine Model

“…Here, we also provided data suggesting that our EPEC infection model was able to activate NFκB via IL-1β, STAT1 via INF-γ, and STAT3 via IL-22 and IL-6, but not CREB. STAT-1 and STAT-3 contribute to the expression of pro-apoptotic and anti-apoptotic genes respectively [57,61]. However, in the present study, it seemed that the response mediated by STAT-1 (whose expression was higher than STAT3 in colon of EPEC-infected mice) prevailed over anti-apoptotic response promoted by STAT3, once increased cleaved caspase, a marker of apoptosis, were detected.…”

“…Similar to IL-6, INF-γ is a pleiotropic protein that promotes the transcription of pro-inflammatory mediators and CXCL10 (by binding to CXCR3 in order to promote the recruitment of monocytes/macrophages and T cells at the site of infection), [57] and were both upregulated in the colon of mice following challenge with EPEC, likely activating STAT1 by binding to INF-γ receptor (INFGR) [58]. In fecal samples from children with symptomatically EPEC infection, intermediate levels of INF-γ have been associated with an increase in infection duration [59].…”

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

“…Among these mediators, chemokines are 8-14-kDa secreted proteins with conserved cysteine residues in their sequences. The chemokine C-X-C motif ligand (CXCL)10, which is also known as interferon (IFN)-γ-inducible protein 10 (IP-10), is a pleiotropic chemokine that belongs to the C-X-C subfamily [10]. As the name implies, this chemokine is secreted by several cell types (e.g., leukocytes, macrophages and endothelial cells) in response to IFN-γ and recruits these cells to sites of infection or inflammation after binding to C-X-C motif receptor (CXCR)3 [10,11].…”

“…The chemokine C-X-C motif ligand (CXCL)10, which is also known as interferon (IFN)-γ-inducible protein 10 (IP-10), is a pleiotropic chemokine that belongs to the C-X-C subfamily [10]. As the name implies, this chemokine is secreted by several cell types (e.g., leukocytes, macrophages and endothelial cells) in response to IFN-γ and recruits these cells to sites of infection or inflammation after binding to C-X-C motif receptor (CXCR)3 [10,11]. The chemokinereceptor pair CXCL10/CXCR3 is widely expressed throughout the central nervous system (CNS) and produces different responses in CNS pathology depending on its expression in different cell types [11][12][13].…”

Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis

“…Recently, CXCL10 has been reported to recruit inflammatory cells and be involved in bone erosion. For example, CXCL10 has been shown to recruit activated T cells which mediate osteoclastogenesis and recruit monocytes, which function as osteoclast precursors, to the inflamed joints [34]. Furthermore, in vivo treatment with antibodies against CXCL10 or its receptor attenuated bone destruction in mice with collagen-induced or adjuvant arthritis [35, 36].…”