# Uncovering and understanding the many functions of ICAM-1 in the lungs during homeostasis and innate immune responses > **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $759,025 ## Abstract Abstract The gene Icam1 codes for intercellular adhesion molecule-1 (ICAM-1, CD54), a member of the Ig-like superfamily of adhesion proteins and a type 1 membrane-bound glycoprotein. It is expressed constitutively on most lung parenchymal cells, functioning as a receptor for interactions between these parenchymal cells and leukocytes. Its major ligands are the four members of the β2 leukocyte integrin family. Our laboratory has contributed to understanding both the adhesive and the signaling functions of ICAM-1. We identified the differential expression of ICAM-1 on AT1 compared to AT2 cells and its upregulation by lipopolysaccharide and S. pneumoniae on these cells and capillary endothelial cells. During inflammatory responses, cytokines such as IL-1, TNF and IFNγ regulate its expression differentially, depending on both the cell type and the inflammatory stimulus. Our studies of its cell-cell adhesive function document its critical roles in pneumonia induced by LPS and P. aeruginosa. Ligation of ICAM-1 by β2 integrins also induces intracellular signaling within both the parenchymal cell and the leukocyte. Furthermore, ICAM-1 is proteolytically shed from the surface of parenchymal cells, and this soluble ICAM1 (sICAM-1) has highly debated functions as an inhibitor of leukocyte adhesion or an activator of leukocytes. Thus, ICAM-1 plays very dynamic roles during inflammatory and immune responses. Due to recently identified issues with the Icam1 null mice generated by homologous recombination and the lack of cell-specific knockouts, we are at a standstill in understanding ICAM-1. We are generating both Icam1 null mice using CRISPR/Cas9 and mice with floxed Icam1 alleles. We will test the hypothesis that membrane-bound and sICAM- 1 mediate a range of cell-cell interactions that depend upon the particular ICAM-1-expressing cell type during both homeostasis and innate immune responses. Aim 1 determines the functions of sICAM-1 in the alveolar space and its therapeutic potential. The role of sICAM-1 in the trafficking of alveolar macrophages along the alveolar surface and the functions of sICAM-1 in recruitment and function of neutrophils and inflammatory macrophages during pneumonia will be identified. Aim 2 determines the functions of ICAM-1 on the alveolar surface during homeostasis and innate immune responses. Mice deficient in ICAM-1 in alveolar epithelial cells will be studied to determine its role in trafficking, motility and function of alveolar macrophages in healthy mice. The effect of alveolar epithelial ICAM-1 in recruitment and function of neutrophils, macrophage subpopulations and NK cells during pneumonia will also be determined. Outside-in signaling initiated by ICAM-1 ligation will also be assessed. Aim 3 determines the functions of endothelial ICAM-1 during innate immune responses. Mice deficient in ICAM-1 expression by endothelial cells will be studied to determine if the leukocytosis observed in Icam1 null mice is due to the absence... ## Key facts - **NIH application ID:** 10981391 - **Project number:** 1R01HL171598-01A1 - **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL - **Principal Investigator:** Claire M Doerschuk - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $759,025 - **Award type:** 1 - **Project period:** 2024-08-26 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10981391 ## Citation > US National Institutes of Health, RePORTER application 10981391, Uncovering and understanding the many functions of ICAM-1 in the lungs during homeostasis and innate immune responses (1R01HL171598-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981391. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*