Brief Exposure of Skin to Near-Infrared Laser Modulates Mast Cell Function and Augments the Immune Response

Abstract

The treatment of skin with low-power continuous wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low-cost, simple, small, and readily translatable compared to the previously explored pulsed wave (PW) medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. Here we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells (MCs) and specific dendritic cell (DC) populations in an established model of intradermal vaccination, and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that CW NIR laser transiently stimulates MCs via generation of reactive oxygen species (ROS), establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ DCs without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR laser to the treatment of immune-related skin diseases.

Laser adjuvant for vaccination

“…Kimizuka et al further revealed that continuous wave 1064 nm laser-induced generation of reactive oxygen species (ROS) in the exposed skin and transiently stimulated mast cells, leading to expression of a defined set of chemokines including CCL2 and CCL20 that ultimately induced CCL21 expression in the lymphatics without overt inflammation. 44 Our group further demonstrated that the immunostimulatory milieu established with the laser exposure induced migrational changes of skin-resident migratory CD103 + DCs, which played a pivotal role in augmentation of the adaptive immune response to the intradermal influenza vaccination (Figure 1). High-fluence low-power laser irradiation (HF-LPLI) has been consistently reported to target cytochrome c oxidase (COX) in electron transport chain (ETC) in mitochondria and induce generation of ROS.…”

“…In this study, it has been suggested that thermal effect played a minimal role as the same dose of 1064 nm laser with a pulsed wave showed limited effects on the DC subsets and immune responses. Kimizuka et al further revealed that continuous wave 1064 nm laser‐induced generation of reactive oxygen species (ROS) in the exposed skin and transiently stimulated mast cells, leading to expression of a defined set of chemokines including CCL2 and CCL20 that ultimately induced CCL21 expression in the lymphatics without overt inflammation . Our group further demonstrated that the immunostimulatory milieu established with the laser exposure induced migrational changes of skin‐resident migratory CD103 + DCs, which played a pivotal role in augmentation of the adaptive immune response to the intradermal influenza vaccination (Figure ).…”

“…High‐frequency UPL induces HSP70 release, while lower frequency UPL creates disarray of the extracellular matrix, but like other adjuvants used in licensed vaccines, both eventually activate key Langerhans cells and APCs in skin . On the other hand, NPL adjuvant induces ROS generation and activation of innate programs including upregulation of a selective set of chemokines, which were not seen in UPL adjuvant, ultimately activating migratory DCs . In contrast to the AFP or NAFL adjuvant, no tissue damage has been detected by histological examination after the UPL or NPL treatment in the human and mouse skin .…”

“…24 On the other hand, NPL adjuvant induces ROS generation and activation of innate programs including upregulation of a selective set of chemokines, which were not seen in UPL adjuvant, 24 ultimately activating migratory DCs. 43,44 In contrast to the AFP or NAFL adjuvant, no tissue damage has been detected by histological examination after the UPL or NPL treatment in the human and mouse skin. 24,26,48 The photoreception mechanisms, exact molecular identity of photoreceptors, and subsequent signaling pathways involved in the adjuvant effect of the UPL or NPL adjuvant remain elusive.…”

Real‐Time Imaging of Vaccine Biodistribution Using Zwitterionic NIR Nanoparticles

“…migDCs migrating into LNs from the peripheral tissues are defined by MHC class II hi CD11c int expression and further divided into Langerin − CD11b − , Langerin − CD11b + , Langerin + CD103 + CD11b − , and Langerin + CD103 − CD11b + Langerhans cells . cDCs are bone‐marrow derived, LN‐resident population and characterized by MHC‐II int CD11c hi expression containing CD11b + (CD8α − ) and CD103 + (CD8α + ) subsets . The number of cDCs and their subpopulations positive for the smaller model vaccines (OVA‐ZW and ONP1) was larger than those for the larger vaccine (ONP2) ( Figure A–C, cDC: OVA‐ZW versus ONP2, P = 0.0109; ONP1 versus ONP2, P = 0.0354; CD103 + cDC, OVA‐ZW versus ONP2, P = 0.0024; ONP1 versus ONP2, P = 0.0439), which reflects the fact that smaller vaccines directly enter the lymphatics and are taken up by cDCs 2c,7,19,26.…”