ICAM-1-CD18 interaction mediates neutrophil cytotoxicity through protease release

Interaction of the beta2-integrin complex on the polymorphonuclear neutrophil (PMN) with intercellular adhesion molecule-1 (ICAM-1) has been implicated in PMN-mediated cytotoxicity. This study examined interaction of the CD11a, CD11b, and CD18 subunits of the beta2-integrin with ICAM-1, transfected into Chinese hamster ovarian (CHO) cells to avoid effects of other adhesion molecules. Incubation of quiescent PMNs with wild-type and ICAM-1-transfected CHO cells produced nominal cell lysis. Similarly, when phorbol myristate acetate (PMA)-activated PMNs were incubated with wild-type CHO cells, minimal cytotoxicity was produced. However, when ICAM-1-transfected CHO cells were incubated with PMA-activated PMNs, 40% cell lysis occurred. Blockade with a monoclonal antibody (MAb) to ICAM-1 or MAbs to CD11a, CD11b, or CD18 reduced PMN-mediated cytotoxicity to baseline. To examine the role of adhesion in cytotoxicity, we studied beta2-integrin-mediated PMN adhesion to ICAM-1-transfected CHO cells and found that MAbs for CD11a, CD11b, and CD18 all abrogated PMN cytotoxicity despite disparate effects on adhesion. To assess the role of CD18, beta2-integrin subunits were cross-linked, and CD18 alone mediated protease release. Moreover, ICAM-1 was immunoprecipitated from transfected CHO cells and incubated with PMNs. This soluble ICAM-1 provoked elastase release, similar to PMA, which could be inhibited by MAbs to CD18 but not MAbs to other beta2-integrin subunits. In addition, coincubation with protease inhibitors eglin C and AAPVCK reduced PMN-mediated cytotoxicity to control levels. Finally, ICAM-1-transfected CHO cells were exposed to activated PMNs from a patient with chronic granulomatous disease that caused significant cell lysis, equivalent to that of PMNs from normal donors. Collectively, these data suggest that ICAM-1 provokes PMN-mediated cytotoxicity via CD18-mediated protease release.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Research article relevant to leech therapy and its derived compounds.

Leech-derived molecules this paper discusses, each with a full profile in the ASH compound registry:

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