Understanding chronic inflammation: couplings between cytokines, ROS, NO, Cai 2+, HIF-1α, Nrf2 and autophagy

Abstract

Chronic inflammation is an important component of many diseases, including autoimmune diseases, intracellular infections, dysbiosis and degenerative diseases. An important element of this state is the mainly positive feedback between inflammatory cytokines, reactive oxygen species (ROS), nitric oxide (NO), increased intracellular calcium, hypoxia-inducible factor 1-alpha (HIF-1α) stabilisation and mitochondrial oxidative stress, which, under normal conditions, enhance the response against pathogens. Autophagy and the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response are mainly negatively coupled with the above-mentioned elements to maintain the defence response at a level appropriate to the severity of the infection. The current review is the first attempt to build a multidimensional model of cellular self-regulation of chronic inflammation. It describes the feedbacks involved in the inflammatory response and explains the possible pathways by which inflammation becomes chronic. The multiplicity of positive feedbacks suggests that symptomatic treatment of chronic inflammation should focus on inhibiting multiple positive feedbacks to effectively suppress all dysregulated elements including inflammation, oxidative stress, calcium stress, mito-stress and other metabolic disturbances.

Keywords: HIF-1α; NF-κB; autophagy; calcium flux; cytokines; iNOS; inflammation; nitric oxide.

Figure 1

The role of the main signalling pathways involved in the inflammatory response: p38, JNK, ERK1/2, PI3K/Akt, AMPK and JAK/STAT. The figure shows the main factors that activate these pathways and their main inflammatory effects. Special attention is given to their influence on autophagy as one of the key processes involved in chronic inflammation. Solid arrows, activation; red dashed lines with •, inhibition. JNK, c-Jun N-terminal kinase; ERK1/2, extracellular signal-regulated kinases 1 and 2; AMPK, AMP-activated protein kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2

The main positive coupling between the inflammation and NOX-derived ROS that drive and amplify the inflammatory response. The main factors involved in this coupling are the transcription factors (NF-κB, AP-1 and NFAT), signalling pathways (p38, PI3K/Akt and ERK1/2) and the protein kinase C (PKC). Solid arrows, activation; red dashed line with •, inhibition; ⊕, the positive coupling between elements. NOX, NADPH oxidase; ROS, reactive oxygen species; NFAT, nuclear factor of activated T cells.

Figure 3

The metabolic couplings between the nitric oxide produced by iNOS and the elements of Positive Coupling System (inflammation/ROS/NO/HIF-1α/Ca_i ²⁺) and with regulatory elements: Nrf2 and autophagy. NO is the double-faced element, as in some cases it amplifies, and in some cases, it controls the inflammatory spiral. Solid arrows, activation; red dashed lines with •, inhibition. iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; NO, nitric oxide; HIF-1α, hypoxia-inducible factor 1-alpha.

Figure 4

The metabolic links between cytosolic Ca²⁺, endoplasmic Ca²⁺, ROS and HIF-1α create the positive couplings that enhance the anti-pathogen response. The details of the couplings with iNOS/NO are in Figure 3 , with autophagy, and Nrf2 in Figure 6 . Solid arrows, activation; red dashed lines with •, inhibition; ⊕, positive coupling between elements; red line crossing out, inhibition of the channel. ROS, reactive oxygen species; HIF-1α, hypoxia-inducible factor 1-alpha; iNOS, inducible nitric oxide synthase; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2.

Figure 5

The metabolic links between HIF-1α and mitochondria. HIF-1α is activated by inflammation, ROS and Ca_i ²⁺. Its activation promotes the pathways that prevent mitochondrial ROS production: HIF-1α activates the anaerobic glycolysis and reduces the number of mitochondria. The positive loop between HIF-1α and succinate enhances the protective effect on mitochondria. Solid arrows, activation; red dashed lines with •, inhibition; ⊕, positive coupling between elements; red line crossing out, inhibition of the channel or pathway. HIF-1α, hypoxia-inducible factor 1-alpha; ROS, reactive oxygen species.

Figure 6

Regulatory role of autophagy and Nrf2 on the Positive Coupling System (PCS; inflammation/ROS/NO/HIF-1α/Ca_i ²⁺). The figure shows the metabolic pathways by which Nrf2 and autophagy control and inhibit the self-excitation of PCS. In two cases, however, the relationship is positive. NF-κB and Nrf2 (marked with x) inhibit each other, and such a double inhibitory coupling serves as a switch between the inflammatory and antioxidant states—activation of one inhibits the other and vice versa. In the case of HIF-1α and Nrf2, the coupling is not quite positive. Nrf2 activates HIF-1α to support the mitochondrial protection provided by HIF-1α. In addition, inhibition of one element also inhibits the other and vice versa, which seems to support the termination of the antiviral response. In the case of the relationship between inflammation and autophagy, both positive and negative couplings are observed. The positive ones seem to enhance the antiviral response in the early phase of infection. The couplings with iNOS/NO are shown in Figure 3 . Solid arrows, activation; red dashed lines with •, inhibition; ⊕, positive coupling; ⊝, negative coupling; ⊗, double-negative coupling. Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; NO, nitric oxide; HIF-1α, hypoxia-inducible factor 1-alpha; iNOS, inducible nitric oxide synthase.