Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae

TY - JOUR

T1 - Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae

AU - Allers, Maaike

AU - Bakker, Petra A

AU - Hoeksma, Jelmer

AU - Spaink, Herman P

AU - den Hertog, Jeroen

N1 - © 2023. Published by The Company of Biologists Ltd.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - PTPN6 encodes SHP1, a protein tyrosine phosphatase with an essential role in immune cell function. SHP1 mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in motheaten mice that lack functional SHP1. To investigate the function of Shp1 in developing zebrafish embryos, we generated a ptpn6 knockout zebrafish line lacking functional Shp1. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development, the myeloid lineage was affected, resulting in a decrease in the number of neutrophils and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher in ptpn6 mutants than in siblings at 5 dpf. Finally, the directional migration of neutrophils and macrophages was decreased in response to wounding, and fewer macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impaired neutrophil and macrophage function, and caused severe inflammation and lethality at the larval stage.

AB - PTPN6 encodes SHP1, a protein tyrosine phosphatase with an essential role in immune cell function. SHP1 mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in motheaten mice that lack functional SHP1. To investigate the function of Shp1 in developing zebrafish embryos, we generated a ptpn6 knockout zebrafish line lacking functional Shp1. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development, the myeloid lineage was affected, resulting in a decrease in the number of neutrophils and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher in ptpn6 mutants than in siblings at 5 dpf. Finally, the directional migration of neutrophils and macrophages was decreased in response to wounding, and fewer macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impaired neutrophil and macrophage function, and caused severe inflammation and lethality at the larval stage.

KW - Animals

KW - Humans

KW - Mice

KW - Inflammation/genetics

KW - Myeloid Cells/metabolism

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics

KW - Zebrafish/metabolism

KW - Larva

U2 - 10.1242/dmm.049715

DO - 10.1242/dmm.049715

M3 - Article

C2 - 36645087

SN - 1754-8403

VL - 16

JO - Disease Models & Mechanisms

JF - Disease Models & Mechanisms

IS - 2

ER -