Chronic Insulin Exposure Induces ER Stress and Lipid Body Accumulation in Mast Cells at the Expense of Their Secretory Degranulation Response.
Lipid bodies (LB) are reservoirs of precursors to inflammatory lipid mediators in immunocytes, including mast cells. LB numbers are dynamic, increasing dramatically under conditions of immunological challenge. We have previously shown in vitro that insulin-influenced lipogenic pathways induce LB biogenesis in mast cells, with their numbers attaining steatosis-like levels. Here, we demonstrate that in vivo hyperinsulinemia resulting from high fat diet is associated with LB accumulation in murine mast cells and basophils. We characterize the lipidome of purified insulin-induced LB, and the shifts in the whole cell lipid landscape in LB that are associated with their accumulation, in both model (RBL2H3) and primary mast cells. Lipidomic analysis suggests a gain of function associated with LB accumulation, in terms of elevated levels of eicosanoid precursors that translate to enhanced antigen-induced LTC4 release. Loss-of-function in terms of a suppressed degranulation response was also associated with LB accumulation, as were ER reprogramming and ER stress, analogous to observations in the obese hepatocyte and adipocyte. Taken together, these data suggest that chronic insulin elevation drives mast cell LB enrichment in vitro and in vivo, with associated effects on the cellular lipidome, ER status and pro-inflammatory responses.
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
William E
WE
Greineisen
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
Kristina
K
Maaetoft-Udsen
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
Mark
M
Speck
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
Januaria
J
Balajadia
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
Lori M N
LM
Shimoda
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America.
Carl
C
Sung
Laboratory of Immunology and Signal Transduction, Chaminade University, Honolulu, Hawaii, United States of America; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
Helen
H
Turner
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001491:Basophils / Q000187:drug effects / Q000378:metabolism; D015550:Cell Degranulation; D002460:Cell Line; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006946:Hyperinsulinism / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010641:Phenotype
D018836:Inflammation Mediators; D007328:Insulin