Impaired Peritoneal Macrophage Function and Delayed Neutrophil Recruitment are Secondary to a Leaky Gut in JAM‐A Deficient Mice
Bibliographic record
Abstract
Junctional adhesion molecule‐A (JAM‐A) is a transmembrane glycoprotein expressed on leukocytes, endothelia and epithelia that regulates endothelial/epithelial barrier function as well as leukocyte transendothelial/transepithelial migration. While biological roles of JAM‐A have been extensively studied with JAM‐A knockout mice ( Jam‐a KO), tissue‐specific JAM‐A deficient animals remain poorly documented. Therefore, we generated mice with tissue selective deletion of JAM‐A in myelomonocytic cells ( LysM‐cre; Jam‐a fl/fl ) and the intestinal epithelium ( Villin‐cre; Jam‐a fl/fl ). We then used an acute peritonitis model induced by intraperitoneal injection of zymosan or lipopolysaccharide (LPS) to study the role of tissue selective expression of JAM‐A in recruitment of polymorphonuclear neutrophils (PMN). Consistent with previous reports, infiltration of PMN into the peritoneum in response to zymosan or LPS was significantly reduced in Jam‐a KO versus Jam‐a WT mice. Surprisingly, in LysM‐cre; Jam‐a fl/fl , the number of PMN recruited into the peritoneum was not affected in response to zymosan nor LPS compared to control littermates, indicating that JAM‐A on PMN is not required for infiltration under such conditions. Importantly, intestinal epithelial‐selective loss of JAM‐A resulted in significant reduction of PMN infiltration in Villin‐cre; Jam‐a fl/fl mice, confirming that extrinsic factors, independent on JAM‐A expression on PMN are necessary for leukocyte recruitment to peritoneum under the conditions studied. We also observed that in response to zymosan or LPS, peritoneal macrophages from Jam‐a KO or Villin‐cre; Jam‐a fl/fl mice produced less of the chemokine CXCL1 and had reduced activity of the transcription factor NFkB. Conversely, peritoneal macrophages from LysM‐cre; Jam‐a fl/fl mice were unaffected compared to Jam‐a fl/fl mice. Given that loss of JAM‐A on intestinal epithelial cells resulted in increased intestinal permeability, we hypothesized that bacterial derived products may impair peritoneal macrophage function. Therefore, experiments were conducted with germ free Villin‐cre; Jam‐a fl/fl mice. We observed that macrophage responses as well as peritoneal recruitment of PMN in response to zymosan or LPS was not affected compared to control mice. These findings suggest that a leaky intestinal barrier and intestinal microbes are critical in regulating systemic neutrophil recruitment through effects on macrophage release of inflammatory mediators. Such observations highlight the functional link between the intestinal barrier, microbiota and the regulation of innate immune responses. Support or Funding Information NIH grants 1R01DK097256 to TLD, DK59888, DK55679 to AN and DK072564, DK061379, and DK079392 to CP. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".