Links between innate immunity and normal tissue radiobiology

Abstract

The body senses "danger" from "damaged self" molecules through members of the same receptor superfamily it uses for microbial "non-self", triggering canonical signaling pathways that lead to the generation of acute inflammatory responses. For this reason, the biology of normal tissue responses to moderate and clinically relevant doses of radiation is inextricably connected to innate immunity. The complex sequence of inflammatory events that ensues causes further cell and tissue damage to eliminate potential invaders but also leads to cytoprotective responses that limit the spread of damage and to wound healing through tissue regeneration or replacement. These sequential processes are orchestrated through multiple feedback control mechanisms involving cyclical production of free radicals and cytokines that are common to both radiation and immune signaling. This requires a concerted effort by resident tissue and inflammatory cell types, with macrophages apparently leading the way. The initial response to moderate doses of radiation therefore feeds into a pro-inflammatory paradigm whose eventual outcome is critically dependent upon the properties of the immune cells that are involved in tissue damage, regeneration and repair and that are in part under genetic influence. Importantly, these canonical pathways provide targets for interventions aimed at modifying normal tissue radiation responses. In this review, we examine areas of intersection between innate immunity and normal tissue radiobiology.

FIG. 1

The Toll-like receptor system. DAMP and PAMP ligands activate dTLRs in the plasma membrane (TLR4/2/1/6/5) or in lysosomal vesicles (TLR3/7/9) through MyD88 or TRIF adapter proteins. NF-κB, AP1 or IRF3/7 transcription factors result in production of pro-inflammatory cytokines and type I interferons.

FIG. 2

The Toll-like receptor system in the intestine. TLR signaling at the epithelial surface can be protective or harmful to barrier function or can assist bacterial translocation to lymph nodes. Microbial products (PAMPS) that pass the barrier stimulate an acute inflammatory response with the release of pro-inflammatory cytokines, DAMPS and PAMPS that cause more inflammation and that license dendritic cells to acquire the ability to present antigens to the adaptive immune system in the lymph nodes and spleen.

FIG. 3

Acute inflammation and its evolution after radiation exposure. Cell death caused by radiation or by the pro-inflammatory cytokines and ROS that are generated cause infiltration of PMNs and macrophages (mϕ) that expand the extent of damage. DAMPS are released that have the ability to generate antigen-specific responses. This may occur for tumor-associated and possibly even self antigens released from damaged normal tissue. Further away from the center of the lesion, cells become protected, angiogenesis is initiated, and a proliferative response ensues with the aim of healing the lesion. The acute inflammatory response transitions to a wound-healing phase accompanied by a decrease in pro-oxidant cytokines and an increase in the antioxidant profile with production of a collagen matrix. This is orchestrated in part by a change in the macrophage phenotype from M1 to M2.