Intestinal stem cells enhance local mucosal immunity through apoptotic body phagocytosis

Zhou, J. Y.; Lu, Q.; Hu, Y.; Fujji, S.; Espenschied, S. T.; Engelhart, M. J.; Lewis, K. J.; Karell, P. E.; Han, Y. T.; Shin, H.; Schmidt, R. E.; Silver, D. J.; Ivanov, A.; Yilmaz, O. H.; Stappenbeck, T.

doi:10.1101/2024.10.29.620856

bioRxiv · 10.1101/2024.10.29.620856

Intestinal stem cells enhance local mucosal immunity through apoptotic body phagocytosis

Zhou, J. Y.·Lu, Q.·Hu, Y.·Fujji, S.·Espenschied, S. T.·Engelhart, M. J.·Lewis, K. J.·Karell, P. E.·Han, Y. T.·Shin, H.·Schmidt, R. E.·Silver, D. J.·Ivanov, A.·Yilmaz, O. H.·Stappenbeck, T.

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Abstract

Modulation of immune tone at mucosal surfaces is critical to maintain homeostasis while facilitating the handling of emerging threats. One dynamic component of immune modulation is the phagocytosis and clearance of apoptotic bodies known as efferocytosis that inhibits inflammation by promoting its resolution. Here, we evaluated the effects of apoptotic body phagocytosis by intestinal epithelial stem and progenitor cells (ISCs). Unexpectedly, instead of immunomodulation through efferocytosis, this process elevated local immune system activity. To achieve this result, ISCs actively engaged apoptotic bodies in a unique fashion, leading to their engulfment and ultimate delivery to lysosomes for processing. We found that ISCs were capable of actively recruiting inert material such as apoptotic bodies by using actin-based intrinsic biomechanical processes. Uptake of apoptotic bodies was facilitated by complement factor C3 produced by apoptotic bodies themselves. ISCs in turn generated signals heightening T cell activity that was driven in part by ISC-generated TNF. Taken together, uptake of apoptotic bodies by ISCs produced a local inflammatory alert to specific immune cells. This altered paradigm for the response to phagocytosed apoptotic bodies fits the needs of active mucosal surfaces and demonstrates that efferocytosis as currently defined is not a universal response of all cell types.

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Zhou, J. Y., Lu, Q., Hu, Y., Fujji, S., Espenschied, S. T., Engelhart, M. J., Lewis, K. J., Karell, P. E., Han, Y. T., Shin, H., Schmidt, R. E., Silver, D. J., Ivanov, A., Yilmaz, O. H., Stappenbeck, T.. 2024-11-03. Intestinal stem cells enhance local mucosal immunity through apoptotic body phagocytosis. https://doi.org/10.1101/2024.10.29.620856

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