# Regulation of Macrophage Activation by House Dust Mite

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

United States (US) soldiers who have served in Iraq show an increased risk for allergic rhinitis and
asthma; soldiers deployed in the Persian Gulf had twice the risk of developing allergic rhinitis as compared to
homeland stationed personnel and 1.6 times the risk of developing asthma. Furthermore, the diagnosis of
asthma with symptoms after the age of 12 years is an exclusion criterion for military enlistment. While the rea-
son for the increased risk for allergic inflammatory diseases has not been established, exposure to high levels
of dust and other inhaled particles is thought to be the most likely explanation. The ubiquitous environmental
allergen, house dust mite (HDM), was found in high levels in the tents of soldiers serving in Iraq and is known
to be a major inducer of asthma. It has been estimated that between 50-80% of rhinitis and asthma is due to
HDM. However, the mechanisms by which HDM induces and exacerbates asthma are not fully understood.
 HDM and many other inhaled particulates contain stimulatory structures we have termed allergen-as-
sociated molecular patterns (AAMPs) that engage and stimulate innate pattern recognition receptors (PRR).
While others have studied the effects of HDM on epithelial and dendritic cells, we have found that HDM directly
activates the macrophage (Mφ) - a cell that is central in the innate immune system and found in abundance in
the lungs and airways. HDM stimulates Mφs to induce the expression of IFNβ and several genes that are char-
acteristic of alternatively-activated Mφs (also termed M2 Mφs), including chitinase family members. We identi-
fied a novel pathway between the induction of IFNβ and caspase 11 that controls chitinase gene expression
and Mφ morphology without inducing high levels of IL-1β or pyroptosis. Furthermore, our preliminary data
show that: (i) HDM stimulates an increase in caspase 11 protein and enzyme activity in a TLR4-independent
manner; (ii) caspase 11 is required for chitinase gene expression and optimal IFNβ induced by HDM in vitro;
(iii) HDM induces a dramatic change in Mφ size and shape with pronounced changes in actin dynamics, {a
response replicated by dust samples from Camp Victory, Iraq; (iv) HDM stimulates expression of protein spe-
cies indicative of autophagy-related processes, such as LC-3 lipidation, without degradative flux;} and (v) we
observed similar HDM-induced changes in human primary Mφs. Thus, our overall goal in this renewal proposal
is to characterize the mechanism by which the non-canonical caspase 11 pathway controls Mφ phenotype and
thus HDM-induced asthma. An understanding of this process is clinically important since human asthmatics
have elevated numbers of M2, as well as increased amounts of chitinase proteins in their blood and airways-
especially during asthma exacerbations. Furthermore, we have shown that M2 initiate and amplify the symp-
toms of asthma in a mouse model.
 The central hypothesis to be tested is that the caspase 11 pathway reg...

## Key facts

- **NIH application ID:** 9898273
- **Project number:** 5I01BX001850-07
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Achsah D. Keegan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898273

## Citation

> US National Institutes of Health, RePORTER application 9898273, Regulation of Macrophage Activation by House Dust Mite (5I01BX001850-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898273. Licensed CC0.

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