Biology subjects

Oberbichler, L.

Publications and source records attributed to Oberbichler, L..

3 recordsLinked to original sources

bioRxiv2024

Unveiling a unique macrophage population in exocrine glands sustained by ILC2-derived GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has a non-redundant role in the emergence and maintenance of alveolar macrophages (AMs). However, its role in developmental and steady-state myelopoiesis outside the lung is largely unexplored. Scanning through developing tissues using a Fate-map and reporter of GM-CSF mouse strain, we discovered that GM-CSF was produced by type 2 innate lymphoid cells (ILC2s) in the submandibular and sublingual salivary gland (SG) during postnatal development. GM-CSF producing ILC2s foster the development of a hitherto undescribed phagocyte subset, which we named adenophages. Detailed analysis focusing on phenotypic and transcriptional profiling revealed that adenophages display shared aspects of both, macrophages and dendritic cells (DCs). We found them to be homogenously distributed across the SG, but always in close proximity to GM-CSF producing ILC2s and myoepithelial cells. Importantly, adenophages were present throughout all analyzed exocrine glands such as lacrimal glands and mammary glands, and were also identified in human SG sections, indicating a conserved role in exocrine glands across species.

immunology↗

bioRxiv2024

Monocyte-derived cells but not Microglia cause Oxidative Tissue Damage in Neuroinflammation

Multiple sclerosis (MS) is characterized by neuroinflammation, oxidative stress, iron toxicity and mitochondrial dysfunction. Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely held to drive tissue damage, yet the specific roles of central nervous system (CNS)- resident versus CNS-invading MPs remain unclear. Here, by combining single-cell profiling with conditional gene targeting, we systematically dissected and interfered with ROS production across CNS MPs in a preclinical model for neuroinflammation. We show that CNS-invading monocyte derived cells (MdCs) exhibit a higher oxidative stress gene signature and produce more ROS compared to CNS-resident microglia. While NADPH oxidase 2 (NOX2), a phagocytic source of ROS, proved redundant, our findings underscore the critical role of mitochondrial ROS (mtROS) in driving oxidative tissue damage. Quenching mtROS through mitocatalase overexpression in MdCs, but not microglia, significantly alleviated neuroinflammation in mice. Thus, our study resolves a longstanding controversy, identifying MdCs as the primary driver of ROS-mediated neuropathology.

immunology↗

bioRxiv2024

Regulatory T cells control type 1-driven immunopathology restraining GM-CSF-producing helper T cells

Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Treg cell depletion or dysfunction rapidly results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion, but the cytokine network underlying immunopathology, and its direct cellular mediators, remain elusive. Here, we combined gene targeting, fate-mapping tools, and high-dimensional cytometry to identify the T helper (TH) cell-derived cytokines and responding cells that execute inflammatory tissue damage upon global loss of peripheral tolerance in mice. We found that TH cell-derived GM-CSF, but not IL-17A, directed the ensuing immunopathology and thereby mortality through recruitment of tissue-invading phagocytes and granulocytes, and enhancement of their reactive oxygen species production and phagocytic proficiency. Our study highlights the critical role of Treg cells in controlling GM-CSF- producing TH cells and type 1-responses to restrain phagocyte-mediated tissue destruction and provides a framework for the use of anti-GM-CSF therapies in patients with chronic inflammatory disorders.

immunology↗