Light Therapy in Patients Undergoing an Operation for a Septic Joint, Necrotizing Soft Tissue Infection, Intraabdominal Sepsis, or Medical Treatment of Pneumonia

The threat of infection is not constant, but rather varies directly with how active we are. This threat is predictable, and for diurnal creatures peaks every 24 hours during the solar day. Not surprising, evolution has prepared us. In the moments preceding daylight, our immune system mobilizes bone marrow leukocytes to populate peripheral tissues and augments leukocyte function. The entire process is orchestrated by the circadian system, and the primary environmental cue is light. Our scientific premise is that the evolutionarily conserved mechanisms of circadian biology confer an immune fitness that can be harnessed and therapeutically applied to treat sepsis.

Within each cell is a circadian clockwork of proteins that dovetails with the molecular machinery regulating cell phenotype. These peripheral clocks are synchronized across the entire organism by the master central clock of the suprachiasmatic nucleus (SCN). Each day, light travels in through the eye to the SCN, and via the autonomic nervous system (ANS), pineal gland, and hypothalamic-pituitary adrenal (HPA) axis, coordinates a temporal program of physiologies, such as enhancing immune competence. This system is maximally entrained by the short wavelength visible blue spectrum. We have applied this blue light in 4 distinct models to reduce tissue injury: ischemia/reperfusion of the liver and kidney, intraabdominal sepsis, and pneumonia. In our studies of sepsis, we identified an optic-parasympathetic pathway through which blue light elevated the expression of the clock protein Rev-Erbalpha within the spleen and bolstered a splenic population of CCR2+ inflammatory monocytes. This enhanced bacterial clearance and increased survival. A Rev-Erbalpha agonist augmented bacterial clearance and prolonged survival, whereas mice deficient in Rev-Erbalpha were no longer protected by blue light, nor were mice that had undergone splenectomy. From these data an innovative paradigm emerges, integrated at the molecular, cellular, and organismal levels, in which circadian pathways regulate cellular clock proteins to optimize the immune niches of the spleen for invading pathogen.

Significance:

Our characterization of the biological mechanisms through which the circadian clock machinery (e.g., Rev-Erbalpha) beneficially alters the cellular response to sepsis provides conceptual and translational innovation to develop novel therapeutics (e.g., blue light) for the treatment of many diseases. It is the logical extension of our prior work showing that blue light in 4 distinct models to reduces enhances immune competence, reduces tissue injury, accelerative bacterial clearance, and improves outcomes: ischemia/reperfusion of the liver and kidney, intraabdominal sepsis, and pneumonia.

Approach: