Blood progenitor redox homeostasis through olfaction-derived systemic GABA in hematopoietic growth control in Drosophila

Abstract

The role of reactive oxygen species (ROS) in myeloid development is well established. However, its aberrant generation alters hematopoiesis. Thus, a comprehensive understanding of events controlling ROS homeostasis forms the central focus of this study. We show that, in homeostasis, myeloid-like blood progenitor cells of the Drosophila larvae, which reside in a specialized hematopoietic organ termed the lymph gland, use TCA to generate ROS. However, excessive ROS production leads to lymph gland growth retardation. Therefore, to moderate blood progenitor ROS, Drosophila larvae rely on olfaction and its downstream systemic GABA. GABA internalization and its breakdown into succinate by progenitor cells activates pyruvate dehydrogenase kinase (PDK), which controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH). PDH is the rate-limiting enzyme that connects pyruvate to the TCA cycle and to oxidative phosphorylation. Thus, GABA metabolism via PDK activation maintains TCA activity and blood progenitor ROS homeostasis, and supports normal lymph gland growth. Consequently, animals that fail to smell also fail to sustain TCA activity and ROS homeostasis, which leads to lymph gland growth retardation. Overall, this study describes the requirement of animal odor-sensing and GABA in myeloid ROS regulation and hematopoietic growth control.

Drosophila Innate Immunity Involves Multiple Signaling Pathways and Coordinated Communication Between Different Tissues

“…Upon olfaction stimulation, a small cluster of neurosecretory cells acting downstream of olfactory receptor neurons releases GABA into hemolymph and binds the GABA B receptor in the MZ, leading to high cytosolic Ca 2+ levels, which maintain blood cell progenitors in the lymph gland (Figure 3) (226). Olfaction-derived systemic GABA also maintains ROS homeostasis in hematopoietic progenitors, which is essential for lymph gland growth (Figure 3) (227). Moreover, odors emitted by wasps induce neurosecretory cell secretion of GABA, which is sensed by the GABA transporter (Gat) in the lymph gland MZ, resulting in the stabilization of Sima protein through intracellular catabolism.…”

Imaginal disc growth factor is involved in melanin synthesis and energy metabolism in Bombyx mori

“…Furthermore, we found several DEGs related to energy metabolism (Figure 4c and Supporting Information: Table ). Glycolysis is the main way for animals to obtain energy; hexokinase, fructokinase, and pyruvate kinase are the three keythree‐key rate‐limiting enzymes (Goyal et al, 2022; Salvucci et al, 1999; Yang et al, 2022). Hexokinase HKDC1 (HKDC1), ATP‐dependent 6‐phosphofructokinase (PFK), and pyruvate kinase (PKLR) were downregulated in the fatbody of BmIDGF mutants.…”

Intrinsic and Extrinsic Regulation of Hematopoiesis in Drosophila

“…The GABA shunt pathway converts imported GABA in immune precursors into succinate to stabilize sima, Drosophila Hif-α, which is required for lamellocyte differentiation. In addition, succinate derived from extrinsic GABA can be utilized in the tricarboxylic acid (TCA) cycle to generate moderate levels of ROS in the LG to promote progenitor maintenance ( Goyal et al, 2022 ). These findings highlight the context-dependent role of GABA in hematopoiesis and immunity.…”