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Abstract
ABSTRACTThe 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.
Highlights
The use of reactive oxygen species (ROS) as a physiological signal in immune progenitor development is apparent both in vertebrates and invertebrates (Bigarella et al, 2014; Harris et al, 2013; PrietoBermejo et al, 2018; Takubo et al, 2013; Tothova et al, 2007; Vincent and Crozatier, 2010)
GABA metabolism in blood progenitor cells controls the overall size of the lymph gland Drosophila lymph gland blood progenitor cells internalize systemic GABA via the GABA transporter (Gat) and catabolize it into succinate via the GABA catabolic pathway (Fig. 1A) (Madhwal et al, 2020)
We observed that the loss of components of the GABA catabolic pathway (Fig. 1A) from blood progenitor cells led to a significant reduction in overall size of the lymph gland (Fig. 1B-D,H)
Summary
The use of reactive oxygen species (ROS) as a physiological signal in immune progenitor development is apparent both in vertebrates and invertebrates (Bigarella et al, 2014; Harris et al, 2013; PrietoBermejo et al, 2018; Takubo et al, 2013; Tothova et al, 2007; Vincent and Crozatier, 2010). Factors governing progenitor maintenance include signaling proteins and metabolites emanating from the local niche (posterior signaling center, PSC), differentiating hemocytes, and systemic cues derived from the brain and fat body (reviewed by Banerjee et al, 2019) These include signaling proteins such as Hh (Mandal et al, 2007), wingless (Sinenko et al, 2009), JAK/STAT (Makki et al, 2010), Dpp (Dey et al, 2016), TGFβ (Makhijani et al, 2017) and insulin (Benmimoun et al, 2012), and metabolites such as lipids (Tiwari et al, 2020), adenosine (Mondal et al, 2011), amino acids (Shim et al, 2012) and GABA (Shim et al, 2013; Madhwal et al, 2020). With these intrinsic features of metabolic and signaling requirements, the lymph gland offers a perfect developmental model with which to gain a comprehensive view of programs that control progenitor ROS homeostasis during hematopoiesis
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