Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation

Braedon McDonald,1 Keir Pittman,1 Gustavo B. Menezes,1* Simon A. Hirota,2 Ingrid Slaba,1Christopher C. M. Waterhouse,1,3 Paul L. Beck,2,4 Daniel A. Muruve,1,4 Paul Kubes1†

Mohamed Antar Aziz2012310880

Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation

IntroductionResults

Discussion

*Sterile inflammation, characterized by redness, heat, swelling, and pain, occurs when tissues are injured in the absence of infection.

*Necrotic cell death can generate profound sterile inflammation characterized by the accumulation of innate immune effector cells, namely neutrophils, within the affected tissue.

* Neutrophils, however, possess a vast arsenal of hydrolytic, oxidative, and pore-forming molecules capable of causing profound collateral tissue destruction. As such, overexuberant neutrophil recruitment in response to sterile inflammatory stimuli contributes to the immunopathology observed in many diseases, including ischemic injuries/infarction, trauma, autoimmunity, drug-induced liver injury, and others.

Introduction

• Therefore, understanding the mechanisms that allow neutrophils to respond to sterile tissue injury and cell death is fundamental to our understanding of both homeostatic innate immune functions and pathogenic immune responses in disease.

* Cell death by necrosis releases multiple endogenous pro-inflammatory damage-associated molecular patterns (DAMPs), including proteins, nucleic acids, extracellular matrix components, and lipid mediators (1, 4, 8–10). When injected into

mice, purified DAMPs or necrotic cells mobilize neutrophils to the site of inoculation.

* In vivo imaging of the early innate immune response to reveal a multistep cascade of molecular events that guide the recruitment of neutrophils to locations of sterile injury.

Results

Neutrophils home in to sites of sterile injury by intravascular crawling.

Accumulation of neutrophils around sites of focal hepatic necrosis

Rapid chemotaxis of neutrophils to sites of sterile injury through the intravascular channels.

Analysis of the microvascular hemodynamics revealed an absence of perfused sinusoids withinthe area of necrosis and occlusion of the sinusoids immediately adjacent to the necrotic core (surrounding ~150 mm) by platelet thrombi.

ATP danger signals initiate neutrophil recruitment via P2X7R signalingand Nlrp3 inflammasome activation.

Thus, ATP danger signals activate a pathway that initiates neutrophil adhesion but do not guide neutrophil chemotaxis toward necrotic cells.

An intravascular chemokine gradient guides neutrophil chemotaxis within the vasculature toward foci of sterile injury.

FPR1-dependent necrotaxis guides precise localization of neutrophils into areas of sterile tissue necrosis.

Discussion

A multi-step hierarchy of intravascular events guide rapid and preciseneutrophil trafficking to areas of sterile injury.