Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes

Abstract

C-reactive protein (CRP) is a member of the pentraxin superfamily that is widely recognized as a marker of inflammatory reactions and cardiovascular risk in humans. Recently, a growing body of data is emerging, which demonstrates that CRP is not only a marker of inflammation but also acts as a direct mediator of inflammatory reactions and the innate immune response. Here, we critically review the various lines of evidence supporting the concept of a pro-inflammatory "CRP system." The CRP system consists of a functionally inert circulating pentameric form (pCRP), which is transformed to its highly pro-inflammatory structural isoforms, pCRP* and ultimately to monomeric CRP (mCRP). While retaining an overall pentameric structure, pCRP* is structurally more relaxed than pCRP, thus exposing neoepitopes important for immune activation and complement fixation. Thereby, pCRP* shares its pro-inflammatory properties with the fully dissociated structural isoform mCRP. The dissociation of pCRP into its pro-inflammatory structural isoforms and thus activation of the CRP system occur on necrotic, apoptotic, and ischemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Both pCRP* and mCRP can cause activation of platelets, leukocytes, endothelial cells, and complement. The localization and deposition of these pro-inflammatory structural isoforms of CRP in inflamed tissue appear to be important mediators for a range of clinical conditions, including ischemia/reperfusion (I/R) injury of various organs, cardiovascular disease, transplant rejection, Alzheimer's disease, and age-related macular degeneration. These findings provide the impetus to tackle the vexing problem of innate immunity response by targeting CRP. Understanding the "activation process" of CRP will also likely allow the development of novel anti-inflammatory drugs, thereby providing potential new immunomodulatory therapeutics in a broad range of inflammatory diseases.

Keywords: Alzheimer disease; C-reactive protein; cardiovascular diseases; inflammation; ischemia/reperfusion.

Figure 1

pCRP is produced by the liver in the context of inflammation and infection in response to cytokines such as interleukin 6 (IL-6) and IL-1β. pCRP can be dissociated into its pro-inflammatory structural isoforms [pCRP* and monomeric CRP (mCRP)] on the surface of activated platelets, leukocytes, endothelial cells, phosphocholine-rich MPs, dying cells, and beta-amyloid. pCRP* and mCRP can activate platelets, leukocytes, and endothelial cells, in addition to activating complement via C1q binding. The pro-inflammatory effects of pCRP*/mCRP can be inhibited with compounds such as bisPC that inhibit the dissociation of pCRP and block mCRP effector binding.

Figure 2

In the setting of myocardial ischemia, the hepatic production of pCRP is upregulated under the regulation of interleukin 6 (IL-6). pCRP circulates in the blood, where it can interact with MPs, activated platelets, leukocytes, and endothelial cells in the ischemic myocardium, which triggers the dissociation of pCRP to its pro-inflammatory forms pCRP* and monomeric CRP (mCRP). In turn, these pro-inflammatory structural isoforms of CRP aggravate tissue injury by promoting the adhesion of leukocytes and platelet deposition to the ischemic endothelium, ultimately resulting in the formation of microvascular thrombi and thus microvascular obstruction. In addition, pCRP*/mCRP enhances leukocyte transmigration where infiltrating leukocytes degranulate and exacerbate tissue injury. pCRP*/mCRP also activate complement, which can directly mediate tissue injury via formation of the membrane attack complex. These pro-inflammatory effects of CRP ultimately result in enhanced myocardial injury and impaired organ function.