Alveolar macrophages (AMs) are central sentinels of the lung that function in pathogen clearance and initiation of inflammatory cascades. Molecular mechanism(s) coupling these two processes are not yet clear. Previous AM depletion studies show both beneficial and detrimental outcomes for pulmonary inflammation and injury, implying a more targeted approach is required for precise modulation of the AM behaviors. Our opportunity in fulfilling this unmet medical need is the identification of the role of TRIM72 in regulating AM phagocytosis and inflammatory signaling pathways. Our pull-down assay identified an interaction between TRIM72 and a novel phagocytic receptor and our data imply that TRIM72 may impact LPS sensing by TLR4. We hypothesize that TRIM72 shapes innate immunity of the lung by regulating CRIg phagocytosis and TLR4 signaling pathway.
We aim to dissect the molecular mechanisms of such regulation in this exploratory grant in two specific aims:
Aim 1 : to delineate the mechanism(s) through which TRIM72 regulates pathogen clearance by AMs, and Aim 2: to explore the mechanism(s) of TRIM72 regulation on TLR4 and the effect of CRIg. Our results should lead to novel discovery on elucidating the role of AMs in pulmonary inflammation and injury and identify new targets for tailored modulation of AM function for the treatment of these lung diseases.

Public Health Relevance

Alveolar macrophages (AMs) are central sentinels of the lung and are important for pathogen clearance and initiation of inflammatory cascades. Our preliminary data suggest that TRIM72 in AMs is required for proper coupling of these two processes through interaction with CRIg. We propose to dissect the underlying mechanism of this coupling for the development of effective therapies targeting different aspects of lung inflammation and injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI133465-01
Application #
9374590
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Davidson, Wendy F
Project Start
2017-05-19
Project End
2019-04-30
Budget Start
2017-05-19
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
$237,282
Indirect Cost
$66,445
Name
Eastern Virginia Medical School
Department
Physiology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Nagre, Nagaraja; Cong, Xiaofei; Ji, Hong-Long et al. (2018) Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair. Am J Respir Cell Mol Biol 59:635-647
Nagre, Nagaraja; Cong, Xiaofei; Terrazas, C├ęsar et al. (2018) Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung. Am J Respir Cell Mol Biol 58:756-766
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