The Acute-Phase Protein PTX3 is an Essential Mediator of Glial Scar Formation and Resolution of Brain Edema after Ischemic Injury

Abstract

Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin-1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood-brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders.

An acidic microenvironment sets the humoral pattern recognition molecule PTX3 in a tissue repair mode

“…formation and reduced blood flow. Collectively, these data indicate that PTX3 plays an essential role in the orchestration of a tissue injury response, in agreement with previous studies (Salio et al, 2008;Norata et al, 2009;Deban et al, 2010;Rodriguez-Grande et al, 2014).…”

Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes

“…6A), four play a role in chemotaxis: CXCL3 (FC=50.3, critical for leukocyte chemotaxis), IL-1α (FC=23.4, recruitment of neutrophils), CCL3 (FC=17.1, recruits T-cells (93)), and CCL4L1/2 (FC=8.1/5.5, trafficking of NK cells (94)). Other genes significantly upregulated in M7 include acute phase protein pentraxin-3 (PTX3, FC=15.3 (95)); ceruloplasmin (CP, FC=3.7) and granzyme A (GZMA, FC=2.2), expressed primarily by NK cells and play a role in host defense (96, 97); and GJA1 (FC=9.6), important for barrier function (98). …”

Astrocyte-Derived Pentraxin 3 Supports Blood–Brain Barrier Integrity Under Acute Phase of Stroke

“…Thus far, several kinds of cell types are confirmed to produce PTX3 - vascular endothelial cells 21, 22 , vascular smooth muscle cells 23 , and monocytes/macrophages 24, 25 . Recent cell culture studies also showed that neurons and mixed glial cells may secrete PTX3 after interleukin-1α/β (IL-1α/β) stimulation 26 . Those inflammation-induced PTX3 may have protective roles since PTX3 can reduce acute myocardial infarction 27 , lung injury 28 , and acute kidney injury 29 .…”

“…Those inflammation-induced PTX3 may have protective roles since PTX3 can reduce acute myocardial infarction 27 , lung injury 28 , and acute kidney injury 29 . Furthermore, PTX3 knockout mice exhibited severe edema formation and glial scar formation under ischemic conditions 26 . Our findings filled the gap of knowledge of PTX3 roles in stroke conditions - (i) reactive astrocytes are the major cell type for PTX3 production in the peri-infarct area, (ii) astrocytic-PTX3 may support BBB integrity, and (iii) PTX3 increases expression levels of tight junction proteins in cerebral endothelial cells.…”