Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila

Abstract

Drosophila hemocytes are akin to mammalian myeloid blood cells that function in stress and innate immune-related responses. A multi-potent progenitor population responds to local signals and to systemic stress by expanding the number of functional blood cells. Here we show mechanisms that demonstrate an integration of environmental carbon dioxide (CO2) and oxygen (O2) inputs that initiate a cascade of signaling events, involving multiple organs, as a stress response when the levels of these two important respiratory gases fall below a threshold. The CO2 and hypoxia-sensing neurons interact at the synaptic level in the brain sending a systemic signal via the fat body to modulate differentiation of a specific class of immune cells. Our findings establish a link between environmental gas sensation and myeloid cell development in Drosophila. A similar relationship exists in humans, but the underlying mechanisms remain to be established.

Intermediate Progenitor cells provide a transition between hematopoietic progenitors and their differentiated descendants

“…The coordinated cell cycle within IPs will provide means for rapid immune response. In this context, the IPs could also provide a platform for rebalancing relative numbers of hemocyte types in response to environmental or internally generated stresses such as nutritional, olfactory, redox stress, injury and immune challenge (Cho et al, 2018;Hao and Jin, 2017;Mukherjee et al, 2011;Owusu-Ansah and Banerjee, 2009;Pastor-Pareja et al, 2008;Rizki and Rizki, 1979;Rizki and Rizki, 1992;Shim et al, 2012;Shim et al, 2013;Small et al, 2014).…”

Drosophilaas a Genetic Model for Hematopoiesis

“…Drosophila blood cells respond to a lack of nutritional content (Benmimoun et al 2012; Dragojlovic-Munther and Martinez-Agosto 2012; Shim et al 2012), lack of favorable odors (Shim et al 2013), or the depletion of environmental CO 2 or O 2 (Cho et al 2018) (Figure 6). The response to a lack of nutrition involves insulin production from the brain and its reception by lymph gland progenitors.…”

“…Hypoxia and low levels of ROS molecules have been known to activate an atypical guanylyl cyclase, Gyc89da (Morton 2004; Evgenov et al 2006; Morton et al 2008; Vermehren-Schmaedick et al 2010). Disruption of any of these three molecules (Gr63a, Gr21a, or Gyc89da) in their respective neurons leads to an increase in lymph gland production of crystal cells (Cho et al 2018).…”

“…This elevated Sima leads to increased production of the Upd3 cytokine in hypoxia-sensing neurons. The inhibition of neuronal expression of either Sima or Upd3 can suppress the increased crystal cell phenotype seen under low CO 2 conditions (Cho et al 2018).…”

“…Decreasing the amount of CO 2 detection leads to high levels of pAKT and p4EBP/Thor throughout the lymph gland. Upregulation of Serrate in the second-instar mutant lymph gland promotes increased crystal cell differentiation (Cho et al 2018). It is through this multisignal and multiorgan relay system that both external gaseous and odiferous ligands are able to affect hematopoietic development to respond to the environment.…”