# Complement and Circadian Interactions in Inflammation and Immunity

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $390,000

## Abstract

ABSTRACT
Circadian (24-hour) rhythms are an essential part of human biology and physiology. A growing number of
studies have shown that disruption of our biological clock is detrimental to health, with night and rotating shift
workers at substantially increased risk of developing numerous disease pathologies, including cancer,
diabetes, obesity, and chronic inflammatory bowel disease. Thus, an understanding of the mechanisms by
which circadian disruption are linked to disease development would be of great benefit to a growing
percentage of the population subjected to circadian disruption of various forms.
Impaired circadian rhythms and gastrointestinal inflammation are directly associated with several leading
digestive tract disorders, including inflammatory bowel disease (IBD). While not well studied in a circadian
context, complement activation and the complement anaphylatoxins, C3a and C5a, have been implicated in
immune dysfunction are tightly linked to the development of numerous diseases, including asthma, cancer,
diabetes, and inflammatory bowel disease. Our preliminary data indicate that the complement anaphylatoxins,
which are phlogistic peptides with critical roles in host defense and the immune response, may provide the link
between circadian disruption and vulnerability to diseases, including gastrointestinal disease. These data
indicate that the complement anaphylatoxins (at the level of the peptides themselves as well as their specific
receptors) are under direct circadian control in vivo and provide circadian modulation of intestinal lymph
exchange in vivo. The overall hypothesis of this application is that the regulation of inflammation and
immunity by the complement system (largely via the complement activation anaphylatoxin peptides) is
greatly affected by disruption of the 24-hour circadian clock leading to dysregulation of the immune
response and normal lymphatic function. Th circadian dependent complement mediated dysfunction
of inflammation and immunity in turn leads to increased disease pathologies, including but not limited
to the development of digestive disorders such as IBD. In support of this hypothesis, novel preliminary
data are presented showing that C5a modulates the cellular content and T-cell polarization in gut lymphoid
tissue in a circadian dependent manner. In addition, the expression of the complement anaphylatoxin
receptors, C3aR and C5aR1, is deficient in Peyer’s patches in a model of circadian-dependent peripheral
arrhythmicity. These data strongly suggest that the C3a/C3aR and C5a/C5aR1 axis is a novel and important
mechanism by which circadian gating of the host lymphatic immune response occurs, and that it is a previously
unknown yet important link between circadian disruption and disease pathologies, including the development
of inflammatory bowel disease. Using circadian mutant models, genetic and environmental manipulation of the
complement system, state of the art imaging, and molecular/bio-analytic...

## Key facts

- **NIH application ID:** 10810865
- **Project number:** 5R01AI158694-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kristin Eckel Mahan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810865

## Citation

> US National Institutes of Health, RePORTER application 10810865, Complement and Circadian Interactions in Inflammation and Immunity (5R01AI158694-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10810865. Licensed CC0.

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