Means and methods for diagnosing and treating inflammatory disorders
Depending on pattern recognition receptors (PRRs) such as toll like receptors (TLRs), the innate immune system can be activated by pathogen associated molecular patterns (PAMPs) like lipopolysaccharides (LPS) or by damage associated molecular patterns (DAMPs; also termed 'alarmins'). DAMPs are endogenous molecules such as cellular proteins, lipids or nucleic acids. DAMP-functions are well described for the members of the calgranulin protein family, S100A8/A9 and S100A12, which are highly overexpressed in certain autoinflammatory diseases where their non-classical cellular release or spontaneous hypersecretion correlates with disease causing genotype and coincides with local as well as systemic inflammatory activity.
We previously demonstrated human mon-cytes to respond to S100A12 stimulation in an exclusively TLR4-dependent manner and have now found that binding of S100A12 to TLR4 and, in particular, the TLR4-dependent inflammatory stimulation requires the organization of the protein into a hexameric ring structure consisting of six similar building blocks. While current anti-inflammatory therapies target cytokines which can arise downstream of TLR4-activation, our structural understanding of the S100A12-TLR4 interaction now allows to specifically target TLR4-activation by an endogenous molecule as an inherent disease perpetuating phenomenon in autoinflammation.
Advantages of the invention
- more precise monitoring of inflammatory processes
- benefit for patients affected by complex genetic autoinflammatory diseases
- development of low-risk therapeutics
Patent applications filed in Europe and USA.