Limiting inflammatory responses
Immune responses induced by PRRs and by antigenspecific receptors are often highly potent and sterilizing. However, they may also be relatively disruptive and can be associated with tissue damage and the requirement for significant tissue repair and energy consumption119. Many of the constitutive immune mechanisms discussed here not only interfere with microbial replication but also have negative effects on PRR activity (Table 1). This raises the possibility that an overarching function of the constitutive immune mechanisms is to both eliminate danger and limit the use of PRR-driven activities. At the mechanistic level, this immunoregulatory function of the constitutive mechanisms can be exerted in two qualitatively different ways. The first is through the direct effect of their antimicrobial activity on decreasing levels of PAMPs. The second is through specific inhibition of PRR signalling.
Reduction of PAMP levels.
Many studies have shown that PRR activation requires PAMP levels to be above a certain threshold25–28. Above this threshold, PRRs are activated in a concentration-dependent manner until saturation is reached. Therefore, constitutive immune mechanisms that reduce PAMP levels will limit or even prevent PRR activation (Fig. 2a). For example, mice deficient in the restriction factor APOBEC3, which has antiretroviral activity, have higher viral loads after infection with murine leukaemia virus and corresponding higher levels of reverse viral transcripts and downstream interferon induction through the cGAS–STING pathway (cyclic GMP–AMP synthase–stimulator of interferon genes pathway)120. Similarly, SAMHD1 activity in vivo controls lentivirus load and limits virus-induced production of interferons in myeloid cells121. In addition, SAMHD1 deficiency leads to increased expression of costimulatory molecules and T cell activation on lentiviral infection, which suggests that the constitutive reduction of PRR activation by SAMHD1 limits not only the expression of innate immune cytokines but also downstream adaptive immune responses121. A third example is provided by the observation that expression of Drosophila Dicer in mammalian cells leads to decreased induction of IFNβ by double-stranded RNA, most likely owing to the digestion of immunostimulatory RNA into shorter 20–25-bp RNA species that activate PRRs only inefficiently122. Finally, constitutive innate immune mechanisms can also reduce PRR activity by lowering the concentration of PAMPs that have immunostimulatory activity. For example, lactoferrin binds CpG DNAs and inhibits their ability to activate TLR9 (ref. 123).
Inhibition of PRR signalling.
In addition to reducing the levels of PAMPs, some constitutive mechanisms have been reported to target PRR activity at the signalling level (Fig. 2a). For example, autophagy negatively regulates signalling by the RIG-I–MAVS pathway (retinoic acid-inducible gene I protein–mitochondrial antiviral signalling protein pathway) and by the cGAS–STING pathway; in the former case by limiting reactive oxygen species-mediated amplification of signalling and by LC3-dependent MAVS inactivation124,125, and in the latter case through degradation of STING126. In line with this, defective autophagy as a result of ATG16L deficiency predisposes to STING-dependent intestinal pathology in mice127, and ATG5 deficiency selectively in neutrophils exacerbates M. tuberculosis immunopathology without affecting bacterial load97. As a second example, lactate, which is produced during aerobic glycolysis and has virus-restricting activity73,74, also directly inhibits MAVS activity; thus lactate both reduces levels of viral PAMPs and has a negative regulatory function to inhibit PAMP-driven signalling and interferon expression128. Third, an engineered amphipathic-helical antimicrobial peptide was found to block TLR4 signalling through the TRIF pathway129. This occurs by the inhibition of TLR4 endocytosis, which is an essential step for the engagement of TRIF from endosomal compartments. Collectively, the current literature suggests that constitutive immune mechanisms reduce PRR activation through a range of mechanisms and, therefore, that these constitutive mechanisms impose a threshold and negative regulatory activity on the amplificative innate and adaptive immune responses (Fig. 2b). We propose that rapid, molecularly specific and non-amplificative responses to challenges provided by constitutive immune mechanisms are beneficial for achieving optimal host defence with minimal immunopathology.
Constitutive immunity beyond infection
Our main focus here has been on infections. However, constitutive immune mechanisms are also involved in the elimination of sterile danger. For example, DNA damage in the nucleus and the accumulation of DNA in extranuclear compartments are eliminated by the DNA damage response and specific DNases130, respectively; the accumulation of misfolded proteins leads to the formation of aggresomes, which are cleared by selective autophagy131,132; excessive accumulation of reactive oxygen species leads to death of the oxygen-stressed cells133; and free cholesterol is converted into an ester derivative by lecithin– cholesterol acyltransferase, thus enabling transport to the liver by high-density lipoprotein and eventual degradation134. Defects in these constitutive and latent danger-eliminating mechanisms lead to the accumulation of danger-associated molecular patterns and activation of PRR-based immunity. For example, in cells with defects in either the DNA damage response or extranuclear DNases, the accumulation of DNA induces type I interferon production through the cGAS–STING pathway135–138. Similarly, defective elimination of protein aggregates or cholesterol leads to the induction of IL-1β production through activation of the NLRP3 inflammasome139,140. Common to all of the examples given above is that the accumulated abnormal endogenous molecules are detected and eliminated through molecularly specific mechanisms independently of PRRs. This elimination limits PRR activation and hence inflammatory reactions. Therefore, in addition to eliminating microorganisms and PAMPs, constitutive immune mechanisms also eliminate sterile danger signals in a damage-limiting manner that prevents the activation of excessive inflammation.