Mechanism On Blood-tissue Exchange Of C-reactive Protein

As a major human acute phase factor and inflammation marker,C-reactive protein(CRP)is mainly synthesized by liver and transported to blood for circulation.CRP was discovered in local lesions such as atherosclerotic plaques and tumors.However,the question about whether local CRP is originated from circulation or in situ synthesis is still unclear.Located at the innermost side of the vascular wall,the endothelial barrier is a key interface that mediates the exchange of substances between blood and extracellular matrix.CRP has a diameter of 10.5 nm and a size that exceeds 3 nm,it has been found that CRP crosses the endothelial barrier through transcytosis.Our experiment on the Transwell with monolayer endothelial cells proved that the transport of CRP has a directional preference from blood to tissue.However,in experiments,we revealed that circulating exogenous CRP that is injected into mice in different ways did not accumulate in the tissues.Later,we observed that the introduction of extracellular matrix that mimics the basement membrane of endothelial cells can reverse the blood-extracellular matrix exchange preference of CRP.Scanning electron microscopy result displayed that the matrix has a molecular sieve structure,and the degree of CRP diffusion on it may be affected by physical thickness.The total of internal reflection imaging further illustrated that CRP that is transported from the blood side to the tissue side could be internalized after exocytosis,and there is a temporal and spatial coupling with the exocytosis event.These studies demonstrated that this reversal is mainly due to the sieve effect that is caused by a porous structure in the extracellular matrix.Therefore,when it is maintained at a high level from the blood side to the extracellular matrix side of the endothelial cells,an immediate reversal of CRP translocation would occur,which could avoid the accumulation of circulating CRP in the extracellular matrix.In addition,we also introduced other typical plasma proteins and porous matrix and determined the sieve effect as a general mechanism to regulate blood-extracellular matrix exchange.The discovery of this mechanism proved that CRP in the local lesions does not originate from circulation but from in situ synthesis,thus emphasizing the importance of studying local CRP.Based on this observation,we have several follow-up studies.We revealed that the locally produced CRP may lead to a slight elevation in the concentration of circulatory CRP associated with disease risk through mouse-related experiments.In addition,recent studies proved that the inflamematory microenvironment in the lesions can induce a monomeric CRP(mCRP)and expose a key part that can mediate the recognition of the pluripotent ligands.We completed a preliminary evaluation of a new model of pluripotent ligand recognition using a competitive binding assay based on this key part.In conclusion,the present study provides a theoretical basis for the exploration of biological functions of CRP and suggests a possible contribution of CRP to disease progression.