Eosinophil—macrophage crosstalk controls obesity-associated adipose inflammation and is stabilized by RELMα in a sex-dependent manner 2309540
TL;DR
Analysis of single cell transcription patterns of eosinophils in the adipose tissue shows that they could be divided into stable subtypes and that the differences between conditions explained the changes and transition between the subtype populations.
Abstract
Eosinophils are immune cells with terminal effector functions in type 2 immune responses, yet recent findings suggest that they exhibit functional plasticity and heterogeneity dependent on tissue-specific cues. 10x Genomics Fixed RNA Profiling was performed on Siglec-F+ purified adipose eosinophils and macrophages from PBS-injected or Nippostrongylus brasiliensis-infected high fat diet-fed male and female C57BL6/J or RELMÉ’-deficient (KO) mice. Through analysis of single cell transcription patterns of eosinophils in the adipose tissue, we show that they could be divided into stable subtypes and that the differences between conditions explained the changes and transition between the subtype populations. Protective eosinophils subtypes, stabilized by the macrophage protein RELMa, dominate in females and with helminth infection and maintain M2 macrophages in a macrophage-eosinophil regulatory loop that protects against obesity through pathways such as CCL6-CCR3, thrombospondin and fibronectin signaling. In contrast, the strength and direction of this regulatory loop is perturbed in males and RELMa deficient mice with a shift to inflammatory M1 macrophages. Validation of the eosinophil subtypes and chemokine/chemokine receptor pairings was performed by spectral flow cytometry and adipose tissue section imaging. Further, through single-cell regulatory network inference and clustering (SCENIC) analysis, we identify transcription factor regulons associated with specific eosinophil subtypes including cell cycle and DNA replication factors (E2F) in C0 and C1 subtypes. Collectively, these results provide a novel way to describe eosinophil heterogeneity and decipher the mechanism underlying changes in eosinophil subtype composition that influence pro-inflammatory or homeostatic effects. Manipulation of the regulons or ligand/receptor interactions provide a powerful opportunity to restore adipose homeostasis in obesity. NIH R21AI180561, NIH R01AI191470, UCR School of Medicine Dean’s Postdoc to Faculty award, TRANSCEND fellowship from the California Institute of Regenerative Medicine (Award # EDUC4-12752). Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)