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HUNDELSHAUSEN LAB

von HUNDELSHAUSEN LAB

We are studying effects of chemokines on platelet activity which is related to atherosclerosis and thrombosis.

We are particularly interested in the fact that chemokines associate with themselves or other soluble mediators to form oligomeric complexes thereby altering the functional behaviour of chemokines.

Our goal is to elucidate the role of chemokines in atherosclerosis and thrombosis resulting in new targets and novel therapeutics.

Philipp von Hundelshausen

LATEST NEWS FROM THE LAB

Launch of the CRC 1784 In Trac : IPEK scientists join in

1 Oct 2026 | News | Funding

CRC 1784 InTrac ➤ IPEK scientists Sabine Steffens, Philipp von Hundelshausen and Christian Wever join the new CRC programme

Steffen Hartmann

We warmly congratulate Julian Leberzammer for Doctoral Prize

30 Jul 2024 | News | Award | Thesis

DOCTORAL PRIZE ➤ Our former colleague Julian Leberzammer wins LMU medical faculty doctoral prize.

Vectormanzone | Vecteezy.com

Arterial thromboses: innovative treatment approach

BlOOD 2022 ➤ IPEK scientists have shown in an animal model that the CXCL12 messenger could be suitable as a target structure for the treatment of blood-clotting disorders

Atherosclerotic vascular disease (ASCVD) is a chronic inflammatory disease of the arterial wall and the prerequisite for plaque erosion and rupture, the pathophysiological substrate of acute coronary syndromes and ischemic stroke which account for the major cause of mortality and disability worldwide.

The results of several clinical trials targeting inflammatory mediators including IL-1β prove that targeting inflammation is worthwhile, but needs to be more specific to avoid immunerelated side effects and preserve efficacy so that further research toward immunomodulatory pathways for atherosclerosis/thrombosis is warranted. Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation.

Until now, these effector molecules have been considered to function independently. We tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectins-1 and -3, we identified several interacting pairs, such as CXCL12 and galectin-3. Based on NMR and MD studies of the CXCL12/ galectin-3 heterodimer, we identified contact sites between CXCL12. Gal-3 attenuated CXCL12-stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation.

Heterodimer by CXCL12-Gal-3 CRD association. (A) The crystal structure of the CXCL12 homodimer (PDB code 4UAI) is shown with one monomer subunit highlighted in green and red. (B) The structure of the Gal-3 CRD (in yellow and red) bound with lactose (in magenta) (PDB code 1A3K) is shown. (C) A model of the heterodimer formed between CXCL12 (green) and Gal-3 (yellow) derived from NMR-directed protein-protein docking, MD simulations and BFE calculations is shown. (D) Spectral expansions of HSQC data of 15N-labelled CXCL12 in the absence (black contours) and presence (red contours) of unlabelled Gal3 CRD are shown. (E) The NMR-based heterodimer model is shown with residues that are most perturbed by interactions between Gal-3 and CXCL12 highlighted in red and orange

Btk is a central signalling molecule in platelets and a potential target in atherothrombosis

Bruton tyrosine kinase inhibitors (BTKi) are used in Bcell malignancies and in development against various autoimmune diseases. Since Btk is also involved in specific pathways of platelet activation, BTKi might be considered to target platelet GPVI/GPIb-mediated atherothrombosis and platelet FcgRIIA-dependent immune disorders. However, BTKi treatment of patients with B-cell malignancies is frequently associated with mild bleeding events caused possibly by off-target inhibition of Tec. We compared the platelet effects of two novel BTKi that exhibit a high (remibrutinib) or low (rilzabrutinib) selectivity for Btk over Tec. We found that Remibrutinib and rilzabrutinib inhibit Btkdependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and FcgRIIA activation. Remibrutinib being more potent and showing a better profile of inhibition of Btk-dependent platelet activation vs. hemostatic impairment than rilzabrutinib may be considered for further development as an antiplatelet drug.