b2 integrins inhibit suppressor of cytokine signaling but also inflammation-associated gene expression in dendritic cells (DC), in line with attenuated T cell activation in autoimmune encephalomyelitis

Heterodimeric b2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In human, loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections.. All available mouse models display a constitutive and ubiquitous knockout of either a or the common b2 (CD18) subunit, which hampers analysis of the cell type-specific role of b2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed efficient knockdown of b2 integrins specifically in dendritic cells (DC). Stimulated b2 integrin-deficient splenic DC showed enhanced cytokine production, and concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as impaired expression of suppressor of cytokine signaling (SOCS) 2-6 as assessed in bone marrow-derived (BM)DC. Paradoxically,, these BMDC also showed attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific b2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove a valuable tool to study leukocyte-specific functions of b2 integrins in vivo. Overall design: We isolated bone marrow cells of CD18fl/fl and CD18?CD11c mice and cultured them for 10 days in GM-CSF containing medium to induce differentiation to dendritic cells (BMDC). BMDC were either treated with 100 ng/mL LPS for 24 h or left untreated. > 10^6 cells of each samples were lysed and total RNA was purified for sequencing.