Mathematical modelling of macrophage and natural killer cell immune response during early stages of peritoneal endometriosis lesion onset

Miller, Claire M., Germano, Domenic P.J., Germano DP, Alicia M. Chenoweth, Holdsworth-Carson S, Sarah J. Holdsworth‐Carson
In: bioRxiv · 2025 · doi:10.1101/2025.01.20.633967 · W4406767139
preprint OA: green CC0 ⤵ 1 in-corpus citation
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This study modeled early peritoneal endometriosis lesion onset, finding that reduced immune cell cytotoxicity, not increased endometrial cell influx, drives disease progression by overwhelming clearance mechanisms.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

This paper develops a compartmental mathematical model of how macrophages and natural killer cells interact with endometrial cells in peritoneal fluid during the early onset of superficial peritoneal endometriosis lesions, emphasizing retrograde influx, immune detection, and clearance. The model shows that increased influx of endometrial cells is associated with heightened pro-inflammatory macrophage activation but does not automatically produce disease, and it evaluates system behavior under changes in immune cytotoxicity and detection capability. The authors predict that reduced immune cytotoxicity is a key driver of transitioning to a diseased state, with hysteresis meaning that returning to a disease-free state requires substantial improvement; the paper also notes added analyses in supplementary material on attachment rates and M2 macrophage upregulation by attached endometrial cells. This paper is centrally about endometriosis — it specifically models early superficial peritoneal lesion onset driven by macrophage and natural killer cell interactions.

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Abstract

Abstract The immune system is hypothesised to contribute to the onset of endometriosis lesions. However, the precise mechanisms underlying its role are not yet known. We introduce a novel compartmental model that describes the interactions between innate immune cells, specifically macrophages and natural killer cells, and endometrial cells, occurring within the peritoneal fluid during the early stages of (superficial peritoneal) endometriosis lesion onset. Our study focuses on retrograde influx, immune detection, and immune clearance. Results show an increased influx of endometrial cells into peritoneal fluid correlates with heightened pro-inflammatory macrophage activation, but does not lead to an increase in disease. We compare the system’s response to changes in immune cytotoxicity and ability to detect ectopic endometrial cells. We predict that reduced cytotoxicity is a key driver of disease. These findings align with the increased immune activation observed clinically. Lastly, we predict that an individual can transition to a diseased state following a reduction in immune system cytotoxicity and/or reduced ability to detect ectopic cells. Due to hysteresis, a significant improvement is then required to restore an individual to the disease-free state. This work provides a valuable framework to explore hypotheses of endometriosis lesion onset and assist in understanding of the disease.
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Abstract The immune system is hypothesised to contribute to the onset of endometriosis lesions. However, the precise mechanisms underlying its role are not yet known. We introduce a novel compartmental model that describes the interactions between innate immune cells, specifically macrophages and natural killer cells, and endometrial cells, occurring within the peritoneal fluid during the early stages of (superficial peritoneal) endometriosis lesion onset. Our study focuses on retrograde influx, immune detection, and immune clearance. Results show an increased influx of endometrial cells into peritoneal fluid correlates with heightened pro-inflammatory macrophage activation, but does not lead to an increase in disease. We compare the system’s response to changes in immune cytotoxicity and ability to detect ectopic endometrial cells. We predict that reduced cytotoxicity is a key driver of disease. These findings align with the increased immune activation observed clinically. Lastly, we predict that an individual can transition to a diseased state following a reduction in immune system cytotoxicity and/or reduced ability to detect ectopic cells. Due to hysteresis, a significant improvement is then required to restore an individual to the disease-free state. This work provides a valuable framework to explore hypotheses of endometriosis lesion onset and assist in understanding of the disease. Competing Interest Statement The authors have declared no competing interest. Footnotes This version of the manuscript has been revised to include additional supplementary material that show the system response under different endometrial cell attachment rates, and the effect of upregulation of M2-type macrophages by attached ednometrial cells on system dynamics.

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Condition tags

endometriosis

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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