Deficiency of NADPH Oxidase Components p47phox and gp91phox Caused Granulomatous Synovitis and Increased Connective Tissue Destruction in Experimental Arthritis Models

Loo, Fons A. J. van de; Bennink, Miranda B.; Arntz, Onno J.; Smeets, Ruben; Lubberts, Erik; Joosten, Leo A. B.; Lent, P.L.E.M. van; Roo, Christina J. J. Coenen-de; Cuzzocrea, Salvatore; Segal, Brahm H.; Holland, Steven M.; Berg, Wim B. van den

doi:10.1016/s0002-9440(10)63509-2

Cited by 84 publications

(70 citation statements)

References 59 publications

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“…It was previously shown, in experiments using zymosan to induce inflammation, that acute peritonitis is dependent on the integrins lymphocyte function-associated antigen 1 and Mac-1, whereas these integrins are not important in joint inflammation (22). Likewise, zymosan can elicit joint inflammation via complement activation (23), but complement is minimally involved in zymosaninduced peritonitis (24). It is therefore possible that, in contrast to the situation in peritonitis, IL-6, though present during the onset of ZIA, does not play a decisive role during this phase of the disease and is overruled by the action of other cytokines.…”

Section: Discussionmentioning

confidence: 99%

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Hooge¹,

Loo²,

Koenders³

et al. 2004

Arthritis & Rheumatism

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Objective. STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT-1, and others have reported preferential activation of STAT-3, in response to endogenous interleukin-6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT-1 and STAT-3 activation in an experimental animal model of arthritis.Methods. Zymosan was injected intraarticularly into naive wild-type (WT), IL-6 ؊/؊ , and STAT-1 ؊/؊ mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene expression of the STATinduced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1 ؊/؊ mice was investigated by reverse transcriptasepolymerase chain reaction.Results. STAT-3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT-1 was observed only during the chronic phase. In IL-6 ؊/؊ mice, STAT activation was limited to STAT-3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL-6 ؊/؊ mice. STAT-1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT-1 ؊/؊ mice, STAT-3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3, gene expression was markedly reduced in STAT-1 ؊/؊ mice.Conclusion. The results in the IL-6 ؊/؊ mice suggest that STAT-3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT-1 ؊/؊ mice suggests an opposing effect of STAT-1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the underlying mechanism by which STAT-1 controls joint inflammation.

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Section: Discussionmentioning

confidence: 99%

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Hooge¹,

Loo²,

Koenders³

et al. 2004

Arthritis & Rheumatism

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“…NOX2-derived ROS are multifaceted regulators of the immune system [8]. Ncf1 knockout mice have been reported to develop symptoms resembling CGD [9] and were also found to develop enhanced arthritis when triggered by zymosan [10] but were protected against EAE [11]. BQ.Ncf1 m1J/m1J mice are more susceptible to EAE and arthritis [5], similar to rats with decreased activity of p47phox and lowered ROS production by the NOX2 complex [12].…”

Section: Introductionmentioning

confidence: 99%

Identification of a region in p47phox/NCF1 crucial for phagocytic NADPH oxidase (NOX2) activation

Sareila

Jaakkola

Olofsson

et al. 2012

Journal of Leukocyte Biology

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A point mutation in the mouse Ncf1 m1J gene decreases production of ROS by the phagocytic NOX2 complex. Three mRNA splice variants are expressed, but only one is expressed as a protein, although at lower levels than the WT NCF1 (also known as p47phox). Our aim was to investigate whether the mutant p47phox, lacking 8 aa, is active, but as a result of its low expression, ROS production is decreased in Ncf1 m1J mice, or whether the mutant p47phox completely lacks the capability to activate the NOX2 complex. The p47phox mutant (⌬228 -235), which was equal to the protein in Ncf1 m1J mice, failed to activate the NOX2 complex. When the deleted region was narrowed down to 2 aa, the p47phox protein remained inactive and failed to translocate to the membrane upon activation. Single amino acid substitutions revealed Thr233 to be vital for ROS production. Residues Tyr231 and Val232 also seemed to be important for p47phox function, as p47phox_Y231G and p47phox_V232G resulted in a Ͼ50% decrease in ROS production by the NOX2 complex. In addition, we identified the epitope of the D-10 anti-p47phox mAb. In conclusion, the p47phox protein variant expressed in Ncf1 m1J mice is completely defective in activating the NOX2 complex to produce ROS, and the effect is dependent on SH3 region amino acids at positions 231-233, which are vital for the proper assembly of the NOX2 complex.

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“…19,20 We found that deficiency in either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex did not influence the severity of Lyme arthritis (Table 3). These experiments show that a complete deficiency in reactive oxygen intermedi- Figure 5.…”

Section: Discussionmentioning

confidence: 89%

“…The finding of van de Loo and colleagues, 19 that NADPH oxidase modulates the severity of zymosan and immunecomplex arthritis in mice and that its absence causes a dramatic increase in arthritis severity suggested that mice lacking a subunit of the NADPH oxidase complex might develop more severe arthritis when infected with B. burgdorferi. Furthermore, we demonstrated that PMNs from severely arthritic C3H/HeN mice generate a lower oxidative burst than PMNs from the mildly arthritic C57BL/6 mice in response to chemotactic peptide (Figure 4).…”

Section: Does the Phagocyte Nadph Oxidase Have A Role In Lyme Arthritmentioning

confidence: 99%

“…Mice deficient in the Ncf1 or Gp91phox subunits of the NADPH oxidase complex developed significantly more severe arthritis than wild-type controls. 19 In addition a splicing mutation of Ncf1, resulting in low levels of truncated Ncf1 protein and a defective oxidative burst response, led to severe collagen-induced chronic arthritis in B10.Q mice. 20 These studies indicate that higher levels of reactive oxygen intermediates can modulate arthritis severity in several animal models.…”

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Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase

Crandall

Dunn

et al. 2005

The American Journal of Pathology

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Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candi- Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi and can involve multiple organs including the joints, heart, skin, and nervous system. 1 Lyme arthritis is a consequence of bacterial invasion of joint tissue and results from localized inflammation triggered by persistent infection. 2,3 Arthritis develops weeks to months after transmission from an infected tick and is characterized by edema, inflammatory cell infiltration, and hyperproliferation of synovium. 1,4,5 In most individuals, arthritis will resolve after clearance of the bacteria, however, a subset of individuals with the most severe inflammatory arthritis have been documented to develop treatment-resistant arthritis that does not respond to antibiotic therapy. 6,7 It is suspected that in these individuals progression to an autoimmune-mediated arthritis more similar to rheumatoid arthritis has occurred. Susceptibility to treatment-resistant arthritis is associated with HLA-DR1*0401, a major histocompatibility complex (MHC) class II allele also associated with rheumatoid arthritis. 6,8,9 These studies suggest that there are two distinct stages of Lyme arthritis; an acute inflammatory arthritis dependent on bacterial invasion and persistence in joint tissues and a chronic, treatment-resistant arthritis that may represent a transition to a rheumatoid-like disease.

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Deficiency of NADPH Oxidase Components p47phox and gp91phox Caused Granulomatous Synovitis and Increased Connective Tissue Destruction in Experimental Arthritis Models

Cited by 84 publications

References 59 publications

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Identification of a region in p47phox/NCF1 crucial for phagocytic NADPH oxidase (NOX2) activation

Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase

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