Nrf2 as a master regulator of tissue damage control and disease tolerance to infection

Abstract

Damage control refers to those actions made towards minimizing damage or loss. Depending on the context, these can range from emergency procedures dealing with the sinking of a ship or to a surgery dealing with severe trauma or even to an imaginary company in Marvel comics, which repairs damaged property arising from conflicts between super heroes and villains. In the context of host microbe interactions, tissue damage control refers to an adaptive response that limits the extent of tissue damage associated with infection. Tissue damage control can limit the severity of infectious diseases without interfering with pathogen burden, conferring disease tolerance to infection. This contrasts with immune-driven resistance mechanisms, which although essential to protect the host from infection, can impose tissue damage to host parenchyma tissues. This damaging effect is countered by stress responses that confer tissue damage control and disease tolerance to infection. Here we discuss how the stress response regulated by the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) acts in such a manner.

Keywords: Nrf2; disease tolerance; infection; oxidative stress; tissue damage control.

Figure 1. Control of Nrf2 activation by different E3 ubiquitin ligase complexes

Acronyms are defined throughout the text. When no longer targeted for degradation by E3 ubiquitin ligase complexes, Nrf2 activity is controlled mainly by its rate of transcription, with newly transcribed Nrf2 regulating gene expression. It is the Keap1–Cul3–Rbx1, Hrd1 E3 ubiquitin ligase and SCF^β-TrCP complexes, however that underlie the stress responsive nature of Nrf2 activity.

Figure 2. Outcomes of Nrf2 activation

Upon infection, activation of Nrf2 in different cellular components of the immune system acts in an immunoregulatory manner, which modulates resistance to infection. Activation of Nrf2 in parenchyma tissues provides tissue damage control and disease tolerance to infection. Control of Nrf2 activation is illustrated in the context of a generic E3 ubiquitin ligase complex, detailed under Figure 2.