da Silva, G. V. L. | Search bioRxiv

bioRxiv2025

Sensory neurons shape macrophage identity via TGF-β signalling

Macrophages play integral roles in maintaining homeostasis and function in their tissues of residence. In the skin, prenatally seeded and highly specialized macrophages physically interact with sensory nerves and contribute to their regeneration after injury. However, mechanisms underlying the development and maintenance of this potentially lifelong commitment of macrophages to nociceptors remain largely elusive. Here, we found that infiltrating myeloid progenitor cells approached the sprouting axons of sensory nerves and gradually adopted a nerve-associated macrophage-like profile. This change in identity was steered and maintained by the immediate microenvironment, in particular TGF-{beta}, which was locally activated by the physical interaction with nerves and integrin-mediated cleavage. Following injury, TGF-{beta} driven specification of macrophages essentially supported nerve regeneration. Overall, we identified TGF-{beta} as a central mediator governing local imprinting and long-term specialization of macrophages in the skin, providing insights into the bidirectional communication between macrophages and sensory nerves.

immunology↗

bioRxiv2024

PD-L1+ Neutrophils mediate Susceptibility during Systemic Inflammatory Response in Non-Alcoholic Fatty Liver Disease

Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD) is a pathological condition affecting many individuals worldwide. Patients with MAFLD are more susceptible to systemic inflammation, including endotoxemia, which accelerates the progressive liver damage. However, the immunological mechanisms that trigger the hyper-inflammatory responses in individuals with MAFLD remain unknown. In the present study, we reported that short-term HFCD (Choline Deficient High Fat Diet)-fed mice, which did not show significant signs of hepatic damage and inflammation in the first two weeks, are more susceptible to a non-severe sepsis-like systemic inflammation induced by LPS challenge. Mechanistically, endotoxemic mice show an excessive accumulation of NK-producing IFN-{gamma} cells in liver tissue, which trigger the recruitment and polarization of a distinct subset of neutrophils, characterized by high expression of PD-L1 and massive release of TNF-. Remarkably, genetic inhibition of IFN-{gamma} or pharmacological blockade of PD-L1 effectively modulated the excessive recruitment of these neutrophils to the liver and TNF- production, thereby preventing hepatic damage and reducing the severity of host mortality. Thus, these results support the design of novel effective strategies to control hyperinflammatory responses in septic HFCD patients and consequently improve their survival.

immunology↗