PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS| JUNE 11, 2020
MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerizationEvelien G. G. Sprenkeler, Stefanie S. V. Henriet, Anton T. J. Tool, Iris C. Kreft, Ivo van der Bijl, Cathelijn E. M. Aarts, Michel van Houdt, Paul J. J. H. Verkuijlen, Koen van Aerde, Gerald Jaspers, Arno van Heijst, Wouter Koole, Thatjana Gardeitchik, Judy Geissler, Martin de Boer, Simon Tol, Christine W. Bruggeman, Floris P. J. van Alphen, Han J. M. P. Verhagen, Emile van den Akker, Hans Janssen, Robin van Bruggen, Timo K. van den Berg, Kian D. Liem, Taco W. Kuijpers
Blood (2020) 135 (24): 2171–2181.
https://doi.org/10.1182/blood.2019002633
Key PointsMKL1-deficient neutrophils show severe functional defects due to defective actin polymerization and downregulation of actin-related proteins.
MKL1 deficiency does not alter primary fibroblast morphology, F-actin content, or migratory behavior.
AbstractMegakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1. The index case died as an infant from progressive and severe pneumonia caused by Pseudomonas aeruginosa and poor wound healing. The younger sibling was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. In addition to the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as a transcriptional coregulator. Degranulation was enhanced upon suboptimal neutrophil activation, whereas production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis or bacterial killing was found. Also, monocyte-derived macrophages showed intact phagocytosis, and lymphocyte counts and proliferative capacity were normal. Nonhematopoietic primary fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and F-actin content, most likely as a result of compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as the most prominent features.
Subjects:
Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis
Topics:
actins, cell motility, neutrophils, polymerization, fibroblasts, primary immune deficiency disorder, acute megakaryocytic leukemias
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