Sterile Injury

Tissue injury results in acute inflammation and activation of the innate immune system. However how the innate immune system detects and orchestrates a response to non-infectious stimuli has not been well defined.

The Kubes lab is actively studying multiple forms of sterile tissue injury in various organs and have discovered novel inflammatory pathways.

Cavity Macrophages

Most eukaryotic organisms have body cavities that surround visceral organs such as the liver, spleen, heart and lung. These body cavities are also home to various immune cells including tissue resident GATA6+ cavity macrophage.

Our lab is interested in uncovering the functional role of these cavity macrophage during homeostasis and diseases such as infection, injury, and cancer.

Recently, we have shown that resident GATA6+ peritoneal cavity macrophage can invade visceral organs such as the liver following a sterile injury. These GATA6+ macrophage were critical for repair of the injured liver.

Wang and Kubes, Cell, 2016

Gata6+ Pericardial Macrophage Are Recruited into the Heart following Cardiac Injury

In addition to the peritoneal cavity, the pericardial cavity that surrounds the heart also contains resident GATA6+ macrophage. These pericardial GATA6+ macrophage also contribute to tissue repair following myocardial infarction.

Deniset et al., Immunity, 2019

Figure. Confocal composite stitch images and 3D projections of Venus+ GPCM within the infarct (zone 1), peri-infarct (zone 2), and remote (zone 3) areas of heart cross-section at 7 days post-MI.


Sterile injury in the liver



Intravascular danger signals guide neutrophils to sites of sterile inflammation

To understand how PMN arrive to sites of sterile inflammation, we have developed a novel thermal injury model of the liver parenchyma and visualized the sinusoidal recruitment of vascular PMN using spinning disk confocal intravital microscopy (Fig 1A, Video). PMN rapidly responded to intravascular danger signals (adenosine triphosphate) and used a hierarchy of distinct directional cues to lead them through healthy liver tissue (chemokine gradient) and then through dead injured liver (formyl-peptide gradient) (Fig 1B and Fig 2).

Injury Figure 1A: (A) Time-lapse images from SD-IVM demonstrating the response of neutrophils (green) to focal hepatic necrosis (red, propidium iodide). Scale bar indicates 200 μm

Injury Figure 1B: (B) Representative SD-IVM images at 2 and 3 hours after injury, demonstrating the intravascular (blue, Alexa-647-BSA) route taken by neutrophils (green) to reach necrotic foci (red). Arrows show path of travel of selected neutrophils. Scale bars, 100 μm

Injury Figure 2

A novel link between vascular brain injury and infection

Patients suffering a non-infectious injury to the brain, either due to blunt trauma or a vascular insult such as a stroke, develop bacterial infections immediately following the injury. This common clinical observation has perplexed physicians and researchers for years. We have investigated how injury to the brain leads to immunosuppression resulting in infection. Using a mouse stroke model we found that rapid and profound immunosuppression occurred because of changes in the behaviour of liver invariant NKT cells. Sympathetic innervation linked the central nervous system to the immune system through its effects on liver iNKT cells. Stimulation of liver iNKT cells promoted a pro-inflammatory response that was protected the host from infection.

References:

  • McDonald B, Kubes P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol. 2012;40(2):157-65.

  • McDonald B, Kubes P. Cellular and molecular choreography of neutrophil recruitment to sites of sterile inflammation. J Mol Med (Berl). 2011 Nov;89(11):1079-88. Epub 2011 Jul 13. Review.

  • McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA, Kubes P. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010 Oct 15;330(6002):362-6. Erratum in: Science. 2011 Mar 25;331(6024):1517.

  • Wong CH, Jenne CN, Lee WY, Léger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011 Oct 7;334(6052):101-5.