Metabolic control of cellular immune-competency by odors in Drosophila

Abstract

Studies in different animal model systems have revealed the impact of odors on immune cells; however, any understanding on why and how odors control cellular immunity remained unclear. We find that Drosophila employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the preconditioned animals elevate their systemic GABA levels leading to the upregulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.

Blood progenitor redox homeostasis through GABA control of TCA cycle inDrosophilahematopoiesis

“…1A) from blood progenitor cells led to a significant reduction in the overall size of the lymph gland . While, defects in lymph gland growth and progenitor homeostasis were evident in our previous study (Madhwal et al, 2020), the mechanism underlying the defects remained unaddressed. In this study, using the similar RNAi mediated genetic knock-down approach, we down-regulated each respective component of the GABA catabolic pathway in blood progenitor cells.…”

“…GABA signaling via GABABR in lymph gland progenitor cells controls their maintenance (Shim et al, 2013) while its utilization as a metabolite regulates progenitor differentiation potential (Madhwal et al, 2020). Intracellularly, GABA catabolism regulates Hif/Sima protein stability in progenitor cells necessary to maintain progenitor responses to infections by parasitic wasps (Madhwal et al, 2020). The current study explores the importance of GABA metabolic pathway in governing TCA activity in the control of progenitor ROS homeostasis.…”

“…Sima functions orthologous to mammalian Hif, where prolyl hydroxylase activity of Hph marks Sima protein for proteasomal mediated degradation. In the presence of GABA, blood progenitor cells stabilize Sima protein, whose downstream target lactate dehydrogenase (Ldh) is known to capacitates blood cells with differentiation potential necessary to respond to parasitic wasp-infections (Madhwal et al, 2020).…”

“…Additionally, recent studies have highlighted important metabolic contributions in blood progenitor development. Progenitor sensing of metabolites derived either locally, like ROS (Owusu-Ansah & , amino acids (Shim et al, 2012), lipids (Tiwari et al, 2020) and adenosine (Mondal et al, 2011) or systemically from neurons (Madhwal et al, 2020;Shim et al, 2013), have been implicated in governing diverse aspects of progenitor development and function. The lymph gland hematopoietic system therefore with its intrinsic feature of metabolic and signaling requirements, offers a perfect developmental model to gain a comprehensive view of metabolic programs controlling progenitor ROS homeostasis in blood development.…”

“…Progenitor cells also rely on GABA, which is neuronally derived upon olfactory stimulation and is sensed by blood cells both as a signaling entity and as a metabolite. GABA signaling via GABABR in lymph gland progenitor cells controls their maintenance (Shim et al, 2013) while its utilization as a metabolite regulates progenitor differentiation potential (Madhwal et al, 2020). Intracellularly, GABA catabolism regulates Hif/Sima protein stability in progenitor cells necessary to maintain progenitor responses to infections by parasitic wasps (Madhwal et al, 2020).…”