Philipp Niethammer

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Verified

Philipp verified their affiliation via an institutional email.

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• PhD
• Faculty Member at Memorial Sloan Kettering Cancer Center

During the innate immune response at epithelial wound sites, oxidative stress acts microbicidal and—mechanistically less well understood—as an immune and resilience signal. The reversible sulfhydryl (SH) oxidation of kinases, phosphatases, and transcription factors constitute the perhaps best-known redox signalling paradigm, whereas mechanisms that...

Generation of reactive oxygen species is an important part of the innate immune response. Generating microbicidal levels of reactive oxygen species (ROS) requires adaptation of mucosal barriers. High tolerance of ROS provides improved innate immune defenses against pathogens, whereas low tolerance renders host cells prone to chronic toxicity and mu...

Leukocytes detect distant wounds within seconds to minutes, which is essential for effective pathogen defense, tissue healing, and regeneration. Blood vessels must detect distant wounds just as rapidly to initiate local leukocyte extravasation, but the mechanism behind this immediate vascular response remains unclear. Using high-speed imaging of li...

Nuclear deformation by osmotic shock or necrosis activates the cytosolic phospholipase A2 (cPla2) nuclear shape sensing pathway, a key regulator of tissue inflammation and repair. Ca²⁺ and inner nuclear membrane (INM) tension (TINM) are believed to mediate nucleoplasmic cPla2 activation. The concept implies that TINM persists long enough to stimula...

The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene expression. As its largest and stiffest organelle, the nucleus also defines the minimal space requirements of a cell. Internal or external pressures that deform a cell to its physical...

Eicosanoids, derived from arachidonic acid (AA), are bioactive lipids with chemokine-like function. While prostaglandin and leukotriene have been extensively studied, the genetics of oxoeicosanoid metabolism remain relatively unexplored. The proto-type oxoeicosanoid 5-KETE is generated from AA by 5-lipoxygenase and the long-elusive redox-sensitive...

**### Simple Gene Correlation Analysis (sGCA) by Permutated Logical Clustering** This is the **standalone version of the Logical Clustering Suite (v1.34) for Win PCs**. Its installation requires download of MATLAB runtime (free) as wrapper. - The Logical Clustering Suite (LCS) clusters gene expression profiles or similar data by permutated logica...

The Logical Clustering Suite (LCS) clusters gene expression profiles or similar data by permutated logical gating according to their “Ideal Phenotypes” (IPs), which are defined by all possible experimental outcomes. Logical clustering conceptually differs from K-means-, SOM, DBSCAN and alike clustering methods that cluster gene expression profiles...

5-oxoETE is a bioactive lipid derived from arachidonic acid generated when phospholipase A2 activation coincides with oxidative stress. Through its G protein-coupled receptor OXER1, pure 5-oxoETE is a potent leukocyte chemoattractant. Yet, its physiological function has remained elusive owing to the unusual OXER1 conservation pattern. OXER1 is cons...

The nuclear membrane may function as a mechanosensory surface alongside the plasma membrane. In this Review, we discuss how this idea emerged, where it currently stands, and point out possible implications, without any claim of comprehensiveness.

Significance A cell must be able to measure whether the lipid membranes that surround its insides are stretched. Currently, mechanosensitive ion channels are the best-studied class of membrane tension sensors, but recent work suggests that peripheral membrane enzymes that gauge nuclear confinement or swelling during cell migration or upon tissue in...

A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00683-0.

The nucleus measures cell confinement with a mechanosensitive phospholipase

Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3–6, ferroptosis is thought to result from the accumulation of unre...

Rapid wound detection by distant leukocytes is essential for antimicrobial defence and post-infection survival1. The reactive oxygen species hydrogen peroxide and the polyunsaturated fatty acid arachidonic acid are among the earliest known mediators of this process2–4. It is unknown whether or how these highly conserved cues collaborate to achieve...

ATP is an important energy metabolite and allosteric signal in health and disease. ATP-interacting proteins, such as P2 receptors, control inflammation, cell death, migration, and wound healing. However, identification of allosteric ATP sites remains challenging, and our current inventory of ATP-controlled pathways is likely incomplete. Here, we de...

Reactive oxygens species (ROS) and polyunsaturated fatty acids (PUFAs) are conserved wound signals throughout phylae. In zebrafish larvae, ROS gradients and osmotically released arachidonic acid mediate rapid wound detection by afar leukocytes. But it is unclear, whether these cues initiate de novo leukocyte recruitment like alarmins or rather ampl...

Quantitative aspects of extracellular H2O2 signaling in animals, such as its spatiotemporal dynamics within tissues, remain little understood. Here we detail an optimized, experimental setup for measuring the dynamics and physiological consequences of extracellular H2O2 application to live tissues by intravital biosensor imaging in zebrafish larvae...

Studying early immune responses to organ damage in situ requires animal models amenable to intravital imaging. Here, we used transparent zebrafish larvae, a powerful animal model for innate immunity, to measure leukocyte recruitment to damaged livers. Bath application of metronidazole (Mtz) to fish expressing nitroreductase (NTR) under a liver-spec...

Tissue damage and infection are deemed likewise triggers of innate immune responses. But whereas neutrophil responses to microbes are generally protective, neutrophil recruitment into damaged tissues without infection is deleterious. Why neutrophils respond to tissue damage and not just to microbes is unknown. Is it a flaw of the innate immune syst...

Evidence emerges that redox gradients regulate morphogenesis, inflammation, regeneration, and healing of tissues. At the example of redox signaling during the zebrafish wound response, I briefly discuss current ideas on how such patterns might be sensed and spatially regulated to guide physiological processes over distances in animals.

Epithelial injury induces rapid recruitment of antimicrobial leukocytes to the wound site. In zebrafish larvae, activation of the epithelial NADPH oxidase Duox at the wound margin is required early during this response. Before injury, leukocytes are near the vascular region, that is, ∼100–300 μm away from the injury site. How Duox establishes long-...

Most research in nuclear mechanotransduction has focused on the nuclear lamina and lamin binding proteins. These structures provide mechanical stability to the nucleus, establish a link between the cytoskeleton and chromatin, and can transmit mechanical signals. At the same time, mechanical perturbations to the nucleus also affect its phospholipid...

Forces deriving from blood flow shear modulate vascular adherence and transendothelial migration of leukocytes into inflamed tissues, but the mechanisms by which shear is sensed are unclear. In this issue, Fine et al. (2016. J. Cell Biol.http://dx.doi.org/10.1083/jcb.201603109 ) identify the guanosine nucleotide exchange factor GEF-H1 as critical f...

Wounding of tissue barriers, such as epithelia, disrupts homeostasis and allows infection. Within minutes, animals detect injury and respond to it by recruitment of phagocytes and barrier breach closure. The signals that activate these first events are scarcely known. Commonly considered are cytoplasmic factors released into the extracellular space...

Many phagocyte behaviors, including vascular rolling and adhesion, migration, and oxidative bursting, are better measured in seconds or minutes than hours or days. Zebrafish is ideally suited for imaging such rapid biology within the intact animal. We discuss how this model has revealed unique insights into various aspects of phagocyte physiology.

Tissue damage activates cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (AA), which is oxidized to proinflammatory eicosanoids by 5-lipoxygenase (5-LOX) on the nuclear envelope. How tissue damage is sensed to activate cPLA2 is unknown. We investigated this by live imaging in wounded zebrafish larvae, where damage of the fin tissue ca...

The intrinsic near-infrared photoluminescence (fluorescence) of single-walled carbon nanotubes exhibits unique photostability, narrow bandwidth, penetration through biological media, environmental sensitivity, and both chromatic variety and range. Biomedical applications exploiting this large family of fluorophores will require the spectral and spa...

The cell nucleus is becoming increasingly recognized as a mechanosensitive organelle. Most research on nuclear mechanosignaling focuses on the nuclear lamina and coupled actin structures. In this commentary, we discuss the possibility that the nuclear membrane senses and transduces mechanical signals similar to the plasma membrane. We briefly summa...

The intrinsic near-infrared photoluminescence (fluorescence) of single-walled carbon nanotubes exhibits unique photostability, narrow bandwidth, penetration through biological media, environmental sensitivity, and both chromatic variety and range. Biomedical applications exploiting this large family of fluorophores will require the spectral and spa...

Nevi harbor some of the same oncogene mutations that also drive malign melanoma. Further tumor promoting events are required to unleash their carcinogenic potential. Using zebrafish whose melanocytes overexpress an HRAS-oncogene, a new study reports that injury induces melanoma, possibly through recruitment of neutrophils that trigger proliferation...

The " gifts " passed down to us by our ancestors are sometimes more, sometimes less flattering-mom's skeptical spirit, dad's sense of duty, but then also: granddad's unfavorably large nose. Traits can help us, or stand in our way depending on how well they are adapted to (and liked by) the people, the environment around us. While the purpose of gra...

Efficient wound healing requires the coordinated responses of various cell types within an injured tissue. To react to the presence of a wound, cells have to first detect it. Judging from their initial biochemical and morphological responses, many cells including leukocytes, epithelial cells, and endothelial cells detect wounds from over hundreds o...

Osmotic cues from the environment mediate rapid detection of epithelial breaches by leukocytes in larval zebrafish tail fins. Using intravital luminescence and fluorescence microscopy, we now show that osmolarity differences between the interstitial fluid and the external environment trigger ATP release at tail fin wounds to initiate rapid wound cl...

Reactive oxygen species (ROS) are generated as a response to cellular stress and regulate processes including cellular signaling and wound healing. In this issue of Developmental Cell, Xu and Chisholm (2014) demonstrate that mitochondrial ROS are required for proper wound healing in Caenorhabditis elegans through controlling the redox state of acti...

How tissue damage is detected to induce inflammatory responses is unclear. Most studies have focused on damage signals released by cell breakage and necrosis. Whether tissues use other cues in addition to cell lysis to detect that they are damaged is unknown. We find that osmolarity differences between interstitial fluid and the external environmen...

H2O2 is a relatively stable, rapidly diffusing reactive oxygen species that has been recently implicated as a mediator of leukocyte recruitment to epithelial wounds and transformed cells in zebrafish. Whether H2O2 activates the innate immune response by acting as a bona fide chemoattractant, enhancing chemoattractant sensing, or triggering producti...

Mitochondria maintain a constant rate of aerobic respiration over a wide range of oxygen levels. However, the control strategies underlying oxygen homeostasis are still unclear. Using mathematical modeling, we found that the mitochondrial electron transport chain (ETC) responds to oxygen level changes by undergoing compensatory changes in reduced e...

Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment o...

Metabolite gradients might guide mitochondrial localization in cells and angiogenesis in tissues. It is unclear whether they can exist in single cells, because the length scale of most cells is small compared to the expected diffusion times of metabolites. For investigation of metabolic gradients, we need experimental systems in which spatial patte...

The cytoplasm of eukaryotic cells is thought to adopt discrete "states" corresponding to different steady states of protein networks that govern changes in subcellular organization. For example, in Xenopus eggs, the interphase to mitosis transition is induced solely by activation of cyclin-dependent kinase 1 (CDK1) that phosphorylates many proteins...

Constructs and Recombinant Proteins Used (A) List of (labeled) recombinant proteins/protein fragments used (left panel) and list of affinity purified antibodies used (right panel). (B) Baculovirus expression and purification of XKCM1-EGFP. Coomassie blue–stained gel of crude Sf9 cells lysate, cleared Sf9 cells lysate, flow through, and eluted XKCM1...

Combined Effects of MAPs Depletion of Aster Size (A) Impact of XMAP215 and XKCM1 depletion (ΔXMAP215/ΔXKCM1) on aster size. Upper panel: immunoblot (IB) of MAPs after indicated treatment. (B) Impact of APC and EB1 depletion (ΔAPC/ΔEB1) on aster size. Upper panel: immunoblot (IB) of MAPs after indicated treatment. (C) Impact of p150glued depletion o...

Recent evidence points at a role of protein interaction gradients around chromatin in mitotic spindle morphogenesis in large eukaryotic cells. Here, we explain how gradients can arise over distances of tens of microns around supramolecular structures from mixtures of soluble molecules. We discuss how coupled sets of such reaction diffusion processe...

The spatial organization of the microtubule cytoskeleton is thought to be directed by steady-state activity gradients of diffusible regulatory molecules. We visualized such intracellular gradients by monitoring the interaction between tubulin and a regulator of microtubule dynamics, stathmin, using a fluorescence resonance energy transfer (FRET) bi...

The neural cell adhesion molecule (NCAM) has been reported to stimulate neuritogenesis either via nonreceptor tyrosine kinases or fibroblast growth factor (FGF) receptor. Here we show that lipid raft association of NCAM is crucial for activation of the nonreceptor tyrosine kinase pathway and induction of neurite outgrowth. Transfection of hippocamp...

In interphase, microtubules form a more or less dynamic network of fibers, usually originating at the centrosome.They play a role in intracellular movement and positioning of organelles (mitochondria, Golgi apparatus, cytoplasmic vesi- cles). When the cell enters mitosis, the interphase network disappears and microtubules start to assemble the mito...