# Innate and Adaptive Immune Consequences of Necroptosis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $254,250

## Abstract

PROPOSAL SUMMARY
The innate immune system responds to perturbations in tissue homeostasis resultant from infection but also
dying cells and tissue damage. Cells die by different modes of programmed cell death including apoptosis and
necroptosis. Cell death by apoptosis is a normal component of healthy tissue physiology that is balanced by cell
division and maintains normal tissue size and function. Cell death by apoptosis is tolerogenic and non-
inflammatory, and contrasts with necroptosis, which is pathological and inflammatory. Necroptosis involves the
formation of a complex of receptor interacting serine/threonine protein kinases RIPK1, RIPK3 and the
necroptosis effector mixed lineage kinase domain-like protein (MLKL). Up until recently, necroptosis was thought
to function primarily in the control of infection and mainly as a fail-safe strategy that counters viral blockade of
apoptosis. Studies in mouse models, however, have shown that deficiency in components of the apoptosis
machinery such as caspase-8 or FADD leads to embryonic lethality driven by necroptosis and dependent on
RIPK3 and MLKL. Other studies using conditional deletion of caspase-8 or FADD in the intestinal epithelium
revealed that blocking the pathways that mediate homeostatic apoptosis precipitates intestinal inflammation
associated with elevated levels of RIPK3 and necroptosis. Indeed, a notable increase in programmed cell death
of intestinal epithelial cells (IEC) has been reported in patients with inflammatory bowel disease (IBD), and this
damage is associated with heightened inflammation and increased levels of tumor necrosis factor (TNF)-a, an
important mediator of cell death. Using a novel mouse model where we can inducibly trigger necroptosis of IEC,
we will determine how IEC necroptosis impacts intestinal homeostasis and we will define the nature of the
inflammatory response. Our previous work has established that homeostatic apoptosis within the intestinal
epithelium is a major driver of immune suppression and tolerance, imprinting intestinal mononuclear phagocytes
(MNP) with ‘suppression of inflammation’ and ‘induction of regulatory CD4 T cell’ transcriptional signatures. Here
we will define how necroptosis impacts MNP responses. We will examine the composition and characteristics of
the small intestinal MNP population that responds to necroptotic IEC and decipher its function in various innate
immune functions relating to the production of inflammatory mediators, modulation of innate lymphoid cell
function as well as the CD4 T helper cell differentiation. The knowledge we gain will define how necroptosis
drives inflammatory responses by innate and adaptive populations of cells, serve as a roadmap for the
consequences of necroptosis in other tissues, and lay the foundation for the development of novel therapeutics
for chronic inflammatory diseases such as IBD.

## Key facts

- **NIH application ID:** 10043494
- **Project number:** 1R21AI154294-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Julie Magarian Blander
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2020-06-17 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043494

## Citation

> US National Institutes of Health, RePORTER application 10043494, Innate and Adaptive Immune Consequences of Necroptosis (1R21AI154294-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10043494. Licensed CC0.

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