The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure

Integrating the pathogenesis of spondyloarthritis: gut and joint united?

Purpose of review : The association between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) is well known. Additionally, about half of SpA patients show microscopic gut inflammation. Substantial progress has been made in understanding the pathogenesis of SpA and IBD, with new therapeutic targets for either of them in clinical development. Recent findings : Microscopic gut inflammation was found in early forms of SpA in about 50% of cases and is associated with age, sex, disease activity and degree of MRI inflammation on sacroiliac joints. Although prospective follow-up data in men and murine animal studies show a parallelism between gut and joint evolution in SpA, therapeutic outcomes are not always the same in SpA and IBD. These differences can be ascribed to differences in not only the cytokine pathways and cells involved in disease, tissue localization and environmental factors but also in pharmacokinetics and biodistribution. Summary : A significant amount of data all point in the direction of arthritis and gut inflammation being pathogenetically closely linked in the SpA concept. However, when it comes to therapeutic effectiveness, the gut and the joints do not always react in the same way. These differences in therapeutic effect could be attributed to the different ways in which cytokine pathways are involved in SpA and IBD

The role of the microbiome in gut and joint inflammation in psoriatic arthritis and spondyloarthritis

Spondyloarthiltis (SpA) encompasses a group of diseases characterized by an inflammatory arthritis involving both joints and entheses. However extraarticular symptoms constitute a large element of the pathology and should not be underestimated. Microscopic gut inflammation is observed in 50% of patients with SpA and has been linked to disease activity, underscoring the effect of gut inflammation in SpA. In this review, we discuss the influence of gut microbiota on SpA pathogenesis. A change m microbiota composition has been linked to the development of various inflammatory arthriti des, and dysbiosis is a potential factor in the pathogenesis of multiple inflammatoty diseases. In this context, several groups have reported the modulatory effects of gut microbiota-derived metabolites on the effect of immune cells. The gut mucosa is populated by several types of regulatory T cells, but also some specialized unconventional innate-like T cells. These cells are predominantly found at mucosal and epithelial barrier sites, wheie they serve an essential lole in modulating host-microbial interplay. Apart from the close association between the composition of the microbiota and inflammatoiy diseases, the therapeutic value of dysbiosis needs further investigation and the identification of a causal inflammatory pathway between gut dysbiosis and musculoskeletal inflammation could revolutionize the therapeutic approach in SpA

Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis

Introduction: Microscopic bowel inflammation is present in up to 50% of patients with spondyloarthritis (SpA) and is associated with more severe disease. Currently no reliable biomarkers exist to identify patients at risk. Calprotectin is a sensitive marker of neutrophilic inflammation, measurable in serum and stool. Objectives: To assess whether serum and faecal calprotectin in addition to C-reactive protein (CRP) can be used to identify patients with SpA at risk of microscopic bowel inflammation. Methods: Serum calprotectin and CRP were measured in 125 patients with SpA. In 44 of these patients, faecal samples were available for calprotectin measurement. All 125 patients underwent an ileocolonoscopy to assess the presence of microscopic bowel inflammation. Results: Microscopic bowel inflammation was present in 53 (42.4%) patients with SpA. Elevated serum calprotectin and CRP were independently associated with microscopic bowel inflammation. Faecal calprotectin was also significantly higher in patients with microscopic bowel inflammation. Patients with CRP and serum calprotectin elevated had a frequency of bowel inflammation of 64% vs 25% in patients with low levels of both. When either CRP or serum calprotectin was elevated, the risk was intermediate (40%) and measuring faecal calprotectin provided further differentiation. Hence we suggest a screening approach where initially serum calprotectin and CRP are assessed and, if necessary, faecal calprotectin. The model using this scenario provided an area under the ROC curve of 74.4% for detection of bowel inflammation. Conclusions: Calprotectin measurements in stool and serum, in addition to CRP, may provide a promising strategy to identify patients with SpA at risk of bowel inflammation and could play a role in overall patient stratification

Inflammatory gene expression in lung tissue and BAL fluid of WT and TNF^ΔARE mice.

<p>mRNA expression of <b>(A)</b> Tnf-α, <b>(C)</b> Tnfr1, <b>(D)</b> Tnfr2, <b>(E)</b> Ccl2, <b>(F)</b> Cxcl1 and <b>(G)</b> Cxcl2 in lung tissue of WT and TNF^ΔARE mice exposed to air or CS during 2 weeks. <b>(B)</b> Protein levels of TNF-α in BAL fluid of WT and TNF^ΔARE mice exposed to air or CS during 2 weeks. mRNA expression of <b>(H)</b> Tnf-α, <b>(J)</b> Tnfr1, <b>(K)</b> Tnfr2, <b>(L)</b> Ccl2, <b>(M)</b> Cxcl1 and <b>(N)</b> Cxcl2 in lung tissue of WT and TNF^ΔARE mice exposed to air or CS during 4 weeks. <b>(I)</b> Protein levels of TNF-α in BAL fluid of WT and TNF^ΔARE mice exposed to air or CS during 4 weeks. Expression levels are relative to the expression of 3 reference genes (hypoxanthine phosphoribosyltransferase 1 (Hprt1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and transferring receptor protein 1 (Tfrc)). Values are expressed as mean ± SEM. * p<0.05, ** p<0.01, *** p<0.001.</p

Mean clinical arthritis score in WT and TNF^ΔARE mice.

<p>Clinical arthritis score during the course of <b>(A)</b> 2 weeks (WT vs. TNF^ΔARE: p < 0,005) and <b>(B)</b> 4 weeks CS exposure (WT vs. TNF^ΔARE: p < 0,005).</p

Histologic score to quantify the degree of ileal inflammation.

<p>PMN: polymorphonuclear cells. ML: mononuclear leukocytes. Hpf: high power field. Scoring scheme adapted from Kontoyiannis et al, 2002.</p><p>Histologic score to quantify the degree of ileal inflammation.</p