NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient.

Autor: Van Bruggen S; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Whitman Center, Marine Biological Laboratory, Chicago University, Woods Hole, MA 02543., Jarrot PA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115., Thomas E; Department of Life Science Technology, Imec, Leuven 3001, Belgium.; Department of Biophysics, Katholieke Universiteit Leuven, Leuven 3000, Belgium., Sheehy CE; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115., Silva CMS; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115., Hsu AY; Department of Pathology, Harvard Medical School, Boston, MA 02115.; Department of Pathology, Dana-Farber/Harvard Cancer Center, Boston, MA 02115.; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA 02115., Cunin P; Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115., Nigrovic PA; Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115., Gomes ER; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon 1649-028, Portugal., Luo HR; Department of Pathology, Harvard Medical School, Boston, MA 02115.; Department of Pathology, Dana-Farber/Harvard Cancer Center, Boston, MA 02115.; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA 02115., Waterman CM; Whitman Center, Marine Biological Laboratory, Chicago University, Woods Hole, MA 02543.; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute of the NIH, Bethesda, MD 20892., Wagner DD; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Whitman Center, Marine Biological Laboratory, Chicago University, Woods Hole, MA 02543.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Aug 29; Vol. 120 (35), pp. e2303814120. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1073/pnas.2303814120
Abstrakt: Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1β and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3 -/- ) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3 -/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.
Databáze: MEDLINE
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