Metabolic adjustment ofDrosophilahemocyte number and sessility by an adipokine

Abstract

In animals, growth is regulated by the complex interplay between paracrine and endocrine signals. When food is scarce, tissues compete for nutrients, leading to critical resource allocation and prioritization. Little is known about how the immune system maturation is coordinated with the growth of other tissues. Here, we describe a signaling mechanism that regulates the number of hemocytes (blood cells) according to the nutritional state of the Drosophila larva. Specifically, we found that the adipokine NimB5 is produced in the fat body upon nutrient scarcity downstream of metabolic sensors. NimB5 is then secreted and bind to hemocytes to down-regulate their proliferation and adhesion. Blocking this signaling loop results in conditional lethality when larvae are raised on a poor diet, due to excessive hemocyte numbers and insufficient energy storage. Similar regulatory mechanisms shaping the immune system in response to nutrient availability are likely to be widespread in animals. Short title: The adipokine NimrodB5 regulates peripheral hematopoiesis in Drosophila Author summaryDrosophila larval hemocytes (blood cells) are found in two compartments: the lymph gland considered as a reservoir, and the peripheral compartment. Peripheral hemocytes form sessile patches attached to the internal surface of the larval body wall or are found freely circulating in the hemolymph. Little is known about the signals that regulate hemocytes proliferation and localization in the peripheral compartment. In this study, we have identified a new gene, NimrodB5, coding for the NimB5 protein, which is secreted by the fat body and binds to hemocytes. NimB5 inhibits hemocyte proliferation while promoting sessility, leading to an increased number of circulating hemocytes and adhesion defects in NimB5 mutant. We show that nimrodB5 expression by the fat body is controlled by metabolic cues to adjust hemocyte number to the physiological state of the larvae.Interestingly, deregulation of NimB5 causes lethality when larvae are raised on a poor diet due to a defect in regulating hemocytes proliferation. In conclusion, we have identified a new adipokine that optimizes hemocytes number to the physiological state of larvae. Our study also reveals a major role of the fat body in peripheral hematopoiesis regulation and outline how it can be costly to maintain a basal immune defense.

Temporal specificity and heterogeneity of Drosophila immune cells

“…This axis is bidirectional. For example, (i) the small secreted peptide Edin produced in the fat body controls the number of plasmatocytes in circulation upon wasp infestation; (ii) the hemocyte expression of the Spaetzle ligand controls the activity of Toll signaling in the fat body and affects the response to infection (Shia et al , ) as well as tumor growth (Parisi et al , ); and (iii) the metabolically induced production of the NimB5 protein from the fat body adjusts the number of hemocytes to the physiological state of the larva (preprint: Ramond et al , ).…”

Subpopulation of Macrophage-Like Plasmatocytes Attenuates Systemic Growth via JAK/STAT in the Drosophila Fat Body

“…Staining for P1, a mature plasmatocyte marker, hnt, a crystal cell marker or L1, a lamellocyte marker, shows that both subpopulations are randomly co-localized with P1 and hnt ( Supplementary Figures 1A-I Hemocyte population size is known to be influenced by changes in internal and external conditions (12,46,55).…”

“…Drosophila hemocytes have been largely classified based on their morphology and expression of a few marker genes (20). Plasmatocytes constitute the largest population and show significant functional diversity; however, it is not clear whether the current classification sufficiently describes possible heterogeneity within plasmatocytes (1,8,12,46). Moreover, the developmental fluctuations within plasmatocytes have not been examined at a cellular level.…”

Temporal specificity and heterogeneity of the fly immune cells’ transcriptional landscape

“…This axis is bidirectional. For example: 1) the small secreted peptide Edin produced in the fat body controls the number of plasmatocytes in circulation upon wasp infestation; 2) the hemocyte expression of the Spaetzle ligand controls the activity of Toll signaling in the fat body and affects the response to infection (Shia et al, 2009) as well as tumor growth (Parisi et al, 2014); 3) the metabolically induced production of the NimB5 protein from the fat body adjusts the number of hemocytes to the physiological state of the larva (Ramond et al, 2019).…”