C-Reactive Protein: Marker of risk for post-traumatic stress disorder and its potential for a mechanistic role in trauma response and recovery

Abstract

Increasing evidence indicates that inflammation plays a role in PTSD and stress disorder pathophysiology. PTSD is consistently associated with higher circulating inflammatory protein levels. Rodent models demonstrate that inflammation promotes enduring avoidance and arousal behaviors after severe stressors (e.g., predator exposure and social defeat), suggesting that inflammation may play a mechanistic role in trauma disorders. C-reactive protein (CRP) is an innate acute phase reactant produced by the liver after acute infection and chronic disease. A growing number of investigations report associations with PTSD diagnosis and elevated peripheral CRP, CRP gene mutations, and CRP gene expression changes in immune signaling pathways. CRP is reasonably established as a potential marker of PTSD and trauma exposure, but if and how it may play a mechanistic role is unclear. In this review, we discuss the current understanding of immune mechanisms in PTSD with a particular focus on the innate immune signaling factor, CRP. We found that although there is consistent evidence of an association of CRP with PTSD symptoms and risk, there is a paucity of data on how CRP might contribute to CNS inflammation in PTSD, and consequently, PTSD symptoms. We discuss potential mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other innate immune signaling factors in modulating trauma responses. Overall, we found that CRP likely contributes to central inflammation, but how it does so is an area for further study.

Keywords: C-reactive protein; biomarker; inflammation; post-traumatic stress disorder.

Figure 1

The potential mechanistic role CRP in trauma response in the periphery and central nervous system. A stressor or inflammatory trigger primes the immune response and the release of inflammatory cytokines, such as IL‐1β or IL‐6, triggering the liver to synthesize CRP. CRP exists in distinct conformational forms, including pCRP and mCRP forms, where fully dissociated mCRP is generally thought to be more proinflammatory towards activating macrophages. Within the peripheral vasculature, CRP activates the complement system and activates monocyte Fcγ receptors to promote macrophage activation, trafficking, and induce the inflammatory signaling cascade. Inflammatory cytokines within this cascade may increase BBB permeability, enhancing macrophage and CRP trafficking into the CNS. CRP can also induce BBB disruption by activating endothelial Fcγ receptors. Microglia and astrocytes also express Fcγ receptors that can be activated by any CRP within the CNS. Both neurons and astrocytes can upregulate CRP expression with acute and chronic inflammatory states. Figure created in the Mind the Graph platform www.mindthegraph.com