Leukocyte adhesion cascade
Leukocyte recruitment is a multistep cascade, and every step is a druggable checkpoint. Inflamed endothelium, activated by TNF and IL-1β through NF-κB (p65), presents P-selectin and E-selectin that catch flowing leukocytes through PSGL-1 and CD44 (tethering and rolling). L-selectin sustains rolling and secondary capture. Endothelial-bound chemokines — CXCL1, CXCL8, CCL2, CCL5, CXCL12, CCL19/CCL21 — engage CXCR2, CCR2, CXCR3, CXCR4 and CCR7, and the released Gαi signal drives PI3Kγ, PLCβ2, Ca2+/DAG, CalDAG-GEFI and Rap1. Rap1 with RIAM delivers talin-1 and kindlin-3 to the β-integrin tail — the inside-out switch that converts bent, low-affinity LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), VLA-4 (CD49d/CD29) and α4β7 into extended, high-affinity receptors for ICAM-1, ICAM-2, VCAM-1 and MAdCAM-1 (firm arrest). Ligated integrins then signal outside-in through Src, Syk, FAK, Pyk2, ADAP–SLP-76, Vav1 and DOCK2 to Rac1, RhoA/ROCK1, WASP–Arp2/3 and myosin-IIA, driving spreading, crawling and finally diapedesis through the PECAM-1, JAM-A, CD99, ESAM and VE-cadherin/claudin-5 junction, assisted by MMP-2/MMP-9. SHARPIN, filamin A and SHP-1 hold the brakes. Click any protein for the matching Assay Genie In Vivo antibody or ELISA kit.
Step 1–2 — endothelial activation, tethering and rolling. TNF and IL-1β activate NF-κB (p65/RelA) in the post-capillary venule endothelium, which transcribes E-selectin (CD62E), ICAM-1 (CD54) and VCAM-1 (CD106) and mobilises preformed P-selectin (CD62P) from Weibel–Palade bodies. Selectins form catch-bonds with the sialomucin PSGL-1 (CD162) and with CD44 on the leukocyte, decelerating the cell from free flow into a slow roll; leukocyte L-selectin (CD62L) mediates secondary capture onto already-adherent cells. Selectin engagement is not passive — PSGL-1 signals through Src and Syk to SLP-76, ADAP and Btk, partially activating LFA-1 and producing the characteristic slow-rolling step. In the gut, the α4β7–MAdCAM-1 pair substitutes for the classical selectin–integrin couple.
Step 3–4 — chemokine triggering, inside-out activation and firm arrest. Chemokines immobilised on endothelial glycosaminoglycans — CXCL1 and CXCL8 for neutrophils, CCL2 and CCL5 for monocytes, CXCL12 for progenitors, CCL19/CCL21 for naive T cells — engage the G-protein-coupled receptors CXCR2, CCR2, CXCR3, CXCR4 and CCR7. Released Gαi activates PI3Kγ and PLCβ2, generating DAG and IP3-driven Ca2+ flux that switches on CalDAG-GEFI and loads Rap1 with GTP. Rap1–RIAM recruits talin-1 (TLN1) and kindlin-3 (FERMT3) onto the CD18 (β2) and CD29 (β1) cytoplasmic tails, separating the α/β transmembrane clasp and extending the ectodomain. High-affinity LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), p150,95 (CD11c/CD18) and VLA-4 (CD49d/CD29) then bind ICAM-1, ICAM-2 and VCAM-1 with enough force to arrest the cell against shear. Loss of kindlin-3 in humans causes leukocyte adhesion deficiency III; loss of CD18 causes LAD-I, which is why this axis is such a clean in-vivo blockade target.
Step 5–6 — outside-in signalling, crawling and diapedesis, and the In Vivo opportunity. Ligand-occupied integrins cluster and signal back inwards through Src and Syk to FAK (PTK2) and Pyk2 (PTK2B), then via Vav1 and DOCK2 to Rac1 and RhoA/ROCK1. WASP and the Arp2/3 complex build the branched lamellipodial actin, myosin-IIA (MYH9) supplies contractility and ezrin plus PIP5K1γ couple the membrane to the cortex, producing Mac-1-dependent luminal crawling to a permissive junction. Transmigration then proceeds through the homophilic junctional receptors PECAM-1 (CD31), JAM-A, CD99 and ESAM, with transient loosening of VE-cadherin and claudin-5 and focal basement-membrane proteolysis by MMP-2 and MMP-9. Negative regulation is built in: SHARPIN binds the integrin α tail to keep it inactive, filamin A competes with talin for the β tail, and SHP-1 recruited to PECAM-1 ITIMs dampens the response. Assay Genie’s In Vivo low-endotoxin range covers this cascade unusually deeply — anti-CD62L, anti-CD162, anti-CD44, anti-CD11a, anti-CD11b, anti-CD11c, anti-CD18, anti-CD49d, anti-CD29, anti-integrin β7, anti-ICAM-1, anti-CD31, anti-CXCR3, anti-CXCR4, anti-TNF and anti-IL-1β — allowing every step from tethering to diapedesis to be blocked in vivo, while ELISA kits quantify the intracellular machinery and the chemokine drivers. For research use only; not for diagnostic or therapeutic procedures.
Every protein node links to a product — In Vivo antibody, ELISA kit or research antibody.