The role of TLR4 and neutrophil expression in infection-triggered arthritis
Bibliographic record
Abstract
The initial response to Chlamydia -induced arthritis probably involves innate immunity but the nature of this interaction has not been defined. In the present study, we examined the role of neutrophils in experimental arthritis in mice with targeted elimination of the small GTPAases Rac1 and Rac2, and the role of toll-like receptors in this model. Arthritis was induced in either wild-type or Rac-deficient mice by intra-articular inoculation of synoviocyte-packaged Chlamydia trachomatis . The scoring of arthritis was assessed by joint swelling and quantitative histopathological scoring. Immunohistochemistry was used to determine the infiltration of neutrophils into the joint. The persistence of Chlamydia in joints of mice after injection was determined by immunoassay. The expression of TLR2 and TLR4 in neutrophils was detected by semiquantitative PCR. Mice genetically deficient in TLR4 were also assessed. In the acute phase, wild-type mice developed more severe arthritis than Rac-deficient mice. At this stage there was abundant infiltration of neutrophils into the joint. In the chronic phase, the Rac-deficient mice developed more severe arthritis and these mice demonstrated defective clearance of the pathogen from the joint. In vitro stimulation of neutrophils with Chlamydia upregulated expression of TLR4 but not TLR3 in wild-type mice. However, neutrophils from Rac-deficient mice did not show this upregulation of TLR4. Sustained TLR4 expression in neutrophils was found to be dependent on expression of Rac. We examined mice genetically deficient in TLR4 expression and demonstrated that such mice developed more severe arthritis than controls. Thus Rac expression plays a profound role in infection-triggered arthritis and demonstrates a bimodal influence on the disease process, exacerabating acute joint inflammation but controlling chronic arthritis. Rac-deficiency was associated with diminished TLR4 expression, impaired host clearance of the pathogen and more severe chronic arthritis. In infection-triggered arthritis, innate immunity plays a critical role. Effective host clearance of an arthritogenic pathogen depends on intact Rac expression by neutrophils and by appropriation of TLR4 by these cells. A defect in this pathway of host defence profoundly influences the outcome of the infection. This study also highlights the changing microenvironment of the joint over time with implications for therapeutic approaches to arthritis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".