Sema7A is crucial for resolution of severe inflammation

Andreas Körner,Alice Bernard,Julia C Fitzgerald,Juan Carlos Alarcon-Barrera,Sarantos Kostidis,Torsten Kaussen,Martin Giera,Valbona Mirakaj

doi:10.1073/pnas.2017527118

Abstract

Endogenous mediators regulating acute inflammatory responses in both the induction and resolution phases of inflammatory processes are pivotal in host defense and tissue homeostasis. Recent studies have identified neuronal guidance proteins characterized in axonal development that display immunomodulatory functions. Here, we identify the neuroimmune guidance cue Semaphorin 7A (Sema7A), which appears to link macrophage (MΦ) metabolic remodeling to inflammation resolution. Sema7A orchestrated MΦ chemotaxis and chemokinesis, activated MΦ differentiation and polarization toward the proresolving M2 phenotype, and promoted leukocyte clearance. Peritoneal MΦSema7A-/- displayed metabolic reprogramming, characterized by reductions in fatty acid oxidation and oxidative phosphorylation, increases in glycolysis and the pentose phosphate pathway, and truncation of the tricarboxylic acid cycle, which resulted in increased levels of the intermediates succinate and fumarate. The low accumulation of citrate in MΦSema7A-/- correlated with the decreased synthesis of prostaglandins, leading to a reduced impact on lipid-mediator class switching and the generation of specialized pro resolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7ASL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.

Highlights

Acute inflammatory responses underlie fundamental pathophysiological mechanisms to protect the host; when these processes become out of control, acute inflammation can lead to collateral tissue destruction and loss of functional organ integrity
We show that the Semaphorin 7A (Sema7A) messenger RNA levels were higher in M-CSF–stimulated M2 MΦs than in GM-CSF–stimulated M1 MΦs (Fig. 1A)
This was associated with increased MΦ expression of the G-protein–coupled receptors ALX/ FPR2 and GPR32, which are known to mediate proresolving actions [14] (Fig. 1E), implying that Sema7A shifted the polarization state toward the M2 phenotype and presumably promoted resolution and metabolic homeostasis [12]

Summary

Introduction

Acute inflammatory responses underlie fundamental pathophysiological mechanisms to protect the host; when these processes become out of control, acute inflammation can lead to collateral tissue destruction and loss of functional organ integrity. Recent evidence indicates that immune cells and metabolic systems are highly coordinated with each other and that this process is critically important for defining cellular function and fate [1, 2] Cells such as monocytes and macrophages (MΦ), which are central modulators/adjustors in the maintenance of tissue homeostasis and repair, undergo metabolic reprogramming in response to inflammatory processes to meet cellular demands such as phagocytosis, proliferation, and cytokine release. Protein microarray analysis revealed suppression of mTOR signaling and activation of phosphorylated AKT2 signaling in peritoneal MΦSema7A−/− Both are critical for the inflammatory response, as they lower oxidative phosphorylation (OXPHOS) levels, activate NF-κB–mediated transcription, and trigger M1 polarization [9]. A.C. is a guest editor invited by the Editorial Board

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Results

Conclusion