β2 Integrins Differentially Regulate Macrophage Polarization, Inflammatory Signaling, and Function: A Prominent Role for CD11d

β2 integrins are leukocyte-specific adhesion receptors that regulate immune cell trafficking and outside-in signaling; however, the individual contributions of their four α subunits, CD11a, CD11b, CD11c, and CD11d, to macrophage activation remain incompletely understood. Here, we investigated the expression dynamics and functional roles of β2 integrins during macrophage polarization by integrating bulk and single-cell RNA-sequencing datasets with transcriptomic, pathway, and functional analyses of individual β2-integrin-deficient macrophages. The four β2-integrin subunits displayed distinct temporal expression patterns during lipopolysaccharide (LPS)-induced macrophage activation and differential expression across M0, M1, and M2 macrophage states. Deletion of individual β2 integrins generally enhanced the M1 transcriptional signature but produced distinct cytokine, chemokine, and functional phenotypes. CD11d deficiency induced one of the most pronounced transcriptional alterations, characterized by increased TNF, interferon, IL-10, JAK-STAT, p53, TGFβ, and WNT signaling, accompanied by reduced hypoxia, MAPK, and PI3K pathway activity. CD11b deficiency preferentially enhanced NF-κB, TNFα, and VEGF signaling while reducing phagocytosis. In contrast, CD11a and CD11c deficiency showed partially convergent transcriptional and MAPK-associated signaling profiles but distinct functional consequences. Analysis of inflammatory and functional signatures further demonstrated integrin-specific regulation of phagocytosis, macrophage activation, differentiation, chemotaxis, and MHC class II-associated programs. Moreover, deletion of individual β2-integrin subunits altered the expression of the remaining family members, revealing a dynamic network of compensatory and antagonistic interactions that became more complex following LPS stimulation. CD11d deficiency was associated with increased inflammatory infiltration during LPS-induced acute lung injury, providing an in vivo correlate of its enhanced inflammatory macrophage phenotype. Together these findings demonstrate that β2 integrins differentially regulate macrophage polarization, signaling, and effector functions rather than acting as functionally redundant adhesion receptors.