Neutrophil granulocyte biology is a central issue of immunological research, but the lack of animal models that allow for neutrophil-selective genetic manipulation has delayed progress. By modulating the neutrophil-specific locus Ly6G with a knock-in allele expressing Cre recombinase and the fluorescent protein tdTomato, we generated a mouse model termed Catchup that exhibits strong neutrophil specificity. Transgene activity was found only in very few eosinophils and basophils and was undetectable in bone marrow precursors, including granulomonocytic progenitors (GMPs). Cre-mediated reporter-gene activation allowed for intravital two-photon microscopy of neutrophils without adoptive transfer. Homozygous animals were Ly6G deficient but showed normal leukocyte cellularity in all measured organs. Ly6G-deficient neutrophils were functionally normal in vitro and in multiple models of sterile or infectious inflammation in vivo. However, Cre-mediated deletion of FcγRIV in neutrophils reduced the cells' recruitment to immune-complex-mediated peritonitis, suggesting a cell-intrinsic role for activating Fc receptors in neutrophil trafficking.

OLV increases the alveolar concentrations of proinflammatory mediators in the ventilated lung. Both desflurane and sevoflurane suppress the local alveolar, but not the systemic, inflammatory responses to OLV and thoracic surgery.

The ␤2-integrin lymphocyte functionassociated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7. IntroductionWithin the immune system, the ␤2-integrin LFA-1 (lymphocyte function-associated antigen; ␣L␤2) mediates T-cell adhesion to the endothelium, homing of T cells to secondary lymphoid organs, and T-cell activation through the interaction of lymphocytes with antigen-presenting cells (APCs). 1,2 On resting T cells, LFA-1 is expressed in an inactive form and adopts a low-affinity conformation for its ligands, the ICAM molecules (inter cell adhesion molecules). 3,4 Triggering of the T-cell receptor (TCR) by Ag/MHC complexes or of the chemokine receptor CCR7 by CCL21 induces a conformational change of LFA-1 that increases its affinity for ICAM-1 (affinity regulation). Furthermore, these stimuli also facilitate clustering of LFA-1, a process termed avidity modulation. 3,4 The molecular events leading to LFA-1 activation have collectively been termed "inside-out signaling."Research of the last decade has revealed that the small GTPase Rap1, the 2 Rap1 effector proteins RIAM (Rap1 interacting adapter molecule) and RAPL (regulator for cell adhesion and polarization enriched in lymphoid tissues), and the RAPL-interacting mammalian Ste20-like kinase (Mst1) are critically involved in TCR-and CCR7-mediated signaling events regulating T-cell adhesion, LFA-1 affinity and avidity modulation, and T-cell-APC interactions. 3,4 Indeed, RAPL-and Mst1-deficient T cells show defects in adhesion, homing, and intranodal migration in vivo. [5][6][7] In addition to RAPL, RIAM, and Mst1, the cytosolic adapter proteins ADAP (adhesion and degranulating promoting adapter protein), and SKAP55 (Src-kinase associated phosphoprotein of 55 kDa) are crucial for i...

Boras et al. demonstrate that Skap2, via interaction with WASp, regulates actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin, thereby being indispensable for β2 integrin activation and neutrophil recruitment.

Our data support the hypothesis that DP8 and/or DP9 represent additional pharmacological targets for the suppression of T cell proliferation and for anti-inflammatory therapy.