title: Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1-mediated neutrophil recruitment during the acute inflammatory response.
abstract: Recruitment of polymorphonuclear neutrophils (PMNs) to sites of acute inflammation critically depends on β2 integrins (CD11/CD18). Recently, the mammalian actin-binding protein 1 (mAbp1) was identified as an important adaptor protein regulating PMN trafficking downstream of β2 integrins. Here, we show that mAbp1 constitutively co-immunoprecipitated with hematopoietic progenitor kinase 1 (HPK1) in neutrophil-like differentiated HL-60 (dHL-60) cells. HPK1 was enriched at the lamellipodium of polarized dHL-60 cells, where it colocalized with mAbp1 and actin. Functional analysis of PMNs from HPK1-deficient mice showed that HPK1 was critical for CXCL1-induced lymphocyte function-associated antigen 1 (LFA-1)-mediated PMN adhesion to ICAM-1 under flow conditions. Accordingly, CXCL1-mediated induction of high-affinity LFA-1 required HPK1, but macrophage antigen 1 (Mac-1) affinity regulation was independent of HPK1. Intravital microscopy of the mouse cremaster muscle confirmed the defect of CXCL1-induced leukocyte adhesion in HPK1-deficient mice. Furthermore, β2 integrin-mediated post-adhesion processes-adhesion strengthening, spreading, and directed mechanotactic crawling of PMNs under flow conditions-involved HPK1 in vitro and in vivo. Upon intrascrotal administration of tumor necrosis factor α (TNF-α), PMN adhesion and extravasation were severely compromised in HPK1-deficient mice. In summary, our results indicate that HPK1 is critically involved in LFA-1-mediated PMN trafficking during acute inflammation.
authors: Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Sascha M
authors: SM
authors: Jakob
authors: Robert
authors: R
authors: Pick
authors: Doris
authors: D
authors: Brechtefeld
authors: Claudia
authors: C
authors: Nussbaum
authors: Friedemann
authors: F
authors: Kiefer
authors: Markus
authors: M
authors: Sperandio
authors: Barbara
authors: B
authors: Walzog
mesh_terms: D000208:Acute Disease; D000210:Acute-Phase Reaction / Q000235:genetics*; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases