# ER-phagy regulation of immune response: mechanisms and significance

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $598,228

## Abstract

Despite increased clinical awareness, sepsis remains a leading cause of death and high healthcare costs
worldwide. Sepsis is a life-threatening condition characterized by an exaggerated immune response to
infection, which can lead to organ dysfunction and even death. However, the inflammatory response pathways
and molecular mechanisms that underlie the disease remain largely unresolved. Autophagy of endoplasmic
reticulum (ER-phagy) serves as a disposal pathway for misfolded proteins and has been implicated in various
diseases, including diabetes, cancer, metabolic diseases, and some neurological disorders. Using ER-phagy
receptor Fam134b knockout mice, we have identified a novel and essential role of ER-phagy in the host
immune response during sepsis. Our findings indicate that depletion of FAM134B entirely abolished NLRP3
(Nucleotide-binding oligomerization domain-Like Receptor containing Pyrin domain 3) inflammasome activation
and the generation of IL-1β in macrophages. Additionally, Fam134b knockout mice exhibited higher survival
rates, less lung injury, lower bacterial load, and lower levels of proinflammatory cytokines in experimental
models of sepsis. Notably, septic patients show upregulation of NLRP3 gene in peripheral blood monocytes
and elevated levels of IL-1β and IL-18 in the blood. We propose the central hypothesis that sepsis induces
macrophage ER-phagy, driving NLRP3 inflammasome activation, cytokine release, and inflammatory tissue
injury. We will use state-of-the-art methods, including intravital microscopy, adoptive macrophage
transplantation, and macrophage RNA sequencing, to investigate these hypotheses and validate them in
human sepsis samples. Our proposal is organized into three specific aims. 1) To define the role of macrophage
ER-phagy in NLRP3 inflammasome activation and lung inflammatory injury during sepsis. 2) To decipher the
molecular mechanisms by which ER-phagy drives NLRP3 inflammasome activation. 3) To test the therapeutic
potential of targeting macrophage ER-phagy for the treatment of septic injury. The successful completion of our
proposed studies has significant potential to impact the future development of novel therapeutic strategies for
bacterial sepsis, ultimately improving patient outcomes and decreasing the burden of this life-threatening
disease on global healthcare systems.

## Key facts

- **NIH application ID:** 10859215
- **Project number:** 1R01HL173334-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Guochang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,228
- **Award type:** 1
- **Project period:** 2024-09-05 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859215

## Citation

> US National Institutes of Health, RePORTER application 10859215, ER-phagy regulation of immune response: mechanisms and significance (1R01HL173334-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10859215. Licensed CC0.

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