Role of Itaconate and Other Metabolites in Anti-Microbial Defense

 Food Fight: Role of Itaconate and Other Metabolites in Anti-Microbial Defense - PMC (nih.gov)

Itaconate is an important metabolite that is involved in immune response as well as controlling inflammation. Krebs cycle.

Implications and Conclusions

Recent findings regarding the role of itaconate in the immune response (Figure 1) not only advance our understanding of cellular immunometabolism, but also represent yet another evolution of its very definition. A precedent has been set for metabolites generated by the host cells to have direct anti-microbial effects. Interestingly, these effects also appear to be coupled with immunoregulatory mechanisms. As we redefine our understanding of the integration of the immune system with cellular metabolism, we will need to consider metabolites in a new light – as molecules with distinct functions as regulators and effectors of immunity. Itaconate may indeed be one of many metabolites with anti-microbial and immunoregulatory functions to be discovered in the future.

The Many Roles of Metabolites in Immunity

There is a growing appreciation that metabolites can have functions in the immune system (and physiology in general) independent of their conventional roles as sources of energy and biomass. While examples of this phenomenon are rapidly growing in number (Table 1), the evolutionary rationale for utilizing metabolites as modulators and effectors of the immune system are not always clear. In general, these non-conventional functions of metabolites fall into several categories.

Table 1

Distinct Functions of Metabolites in the Immune System

Metabolite	Mediator	Function	Reference
Beta-hydroxybutyrate	GPR109A	Anti-inflammatory effect in murine macrophages and human monocytes in vitro	(Digby et al., 2012; Zandi-Nejad et al., 2013)
		Reduce recruitment of macrophages to atherosclerotic plaques	(Lukasova et al., 2011)
		Reduce inflammatory infiltrate into the brain in stroke and EAE models	(Chen et al., 2014; Rahman et al., 2014)
	Unknown	Inhibit inflammasome activation	(Youm et al., 2015)
Lactate	GPR81	Reduce inflammasome activation	(Hoque et al., 2014)
	HIF1α-dependent mechanism	Promote M2 polarization of macrophages	(Colegio et al., 2014)
Itaconate	Inhibition of glyoxylate cycle	Bacteriostatic and bactericidal, anti-fungal	(Lorenz and Fink, 2001; McFadden and Purohit, 1977; McKinney et al., 2000; Michelucci et al., 2013; Muñoz-Elías and McKinney, 2005; Naujoks et al., 2016)
	Inhibition of SDH	Limit ROS production, antiinflammatory	(Lampropoulou et al., 2016)
	Unknown	Potentiate anti-inflammatory effects of HO-1	(Jamal Uddin et al., 2015)
	Unknown	Promote ROS production in murine viral infection and zebrafish bacterial infection	(Hall et al., 2013; Ren et al., 2016)
Short-chain fatty acids (Acetate, Butyrate, Propionate) (Microbiota-derived)	GPR43	Promotes inflammatory resolution, inhibits immune cell infiltration in models of colitis, arthritis, and asthma	(Maslowski et al., 2009)
		Inflammasome activation and protection against colitis model	(Macia et al., 2015)
	GPR109A	Anti-inflammatory effect on colonic macrophages and dendritic cells	(Singh et al., 2014)
	GPR41	Promote allergic inflammation	(Trompette et al., 2014)
	HDAC inhibition	Anti-inflammatory effect on macrophages	(Chang et al., 2014)
		Promote apoptosis in T cells	(Zimmerman et al., 2012)
	Unknown	Promote regulatory T cell differentiation	(Arpaia et al., 2013; Furusawa et al., 2013)
Sterols	LXR	Pro-inflammatory, prosurvival effect in macrophages, proproliferative effect in T cells	(Bensinger et al., 2008; Joseph et al., 2003, 2004)
		Promotes protection against MTB infection	(Korf et al., 2009)
		Coordinates neutrophil homeostasis	(Hong et al., 2012)b
7α,25-dihydroxycholesterol	EBI2 (GPR183)	Directs B and T cell migration and localization	(Hannedouche et al., 2011; Li et al., 2016; Liu et al., 2011; Pereira et al., 2009; Yi et al., 2012)
		Negative regulator of type I interferons in DCs	(Chiang et al., 2013)
25-hydroxycholesterol	Unknown	Amplifies inflammatory signaling in macrophages	(Gold et al., 2014)
	Antagonizing SREPB processing	Suppress IL-1β driven inflammation	(Reboldi et al., 2014)
Succinate	HIF1adependent mechanism	Promote IL-1β expression	(Tannahill et al., 2013)
	GPR91	Enhance dendritic cell priming of adaptive immune response	(Rubic et al., 2008)
Tryptophan metabolites (Can be microbiotaderived or endogenously produced)	Unknown	Suppress T cell and NK cell proliferation and function	(Della Chiesa et al., 2006; Frumento et al., 2002; Munn et al., 1999; Terness et al., 2002)
		Inhibit anti-cancer immune response	(Muller et al., 2005; Uyttenhove et al., 2003)
		Promote regulatory T cell generation by dendritic cells	(Chen et al., 2008)
	AHR	Anti-inflammatory effect in macrophages	(Kimura et al., 2009)
		Promote Th17 differentiation	(Kimura et al., 2008; Veldhoen et al., 2008, 2009)
		Promote type 1 regulatory T cells and Foxp3+ regulatory T cells	(Apetoh et al., 2010; Gandhi et al., 2010)
		Maintain intraepithelial lymphocytes in the gut	(Li et al., 2011)
		Maintain ILC3s in the gut	(Qiu et al., 2012)
		Maintain IL22-secreting ILCs	(Lee et al., 2012)
		Reduce astrocyte inflammation and protect against EAE	(Rothhammer et al., 2016)
ω-3 Fatty acids	GPR120	Anti-inflammatory effect in macrophages	(Oh et al., 2010)
Medium chain fatty acids	GPR84	Pro-inflammatory in human peripheral mononuclear cells	(Suzuki et al., 2013)
		Negatively regulates IL-4 production in T cells in vitro	(Venkataraman and Kuo, 2005)

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First, metabolites can be used as signals ‘reporting’ on the energy status of the organism. The immune response can be energetically costly and may siphon nutrients from a shared resource pool. While such a sacrifice may be acceptable in well-nourished states, an exuberant immune response is likely incompatible with a nutrient-deprived state (Okin and Medzhitov, 2012). Ketone bodies provide a good example of metabolites that perform signaling function reporting on organismal metabolic state (Newman and Verdin, 2014). Thus, beta-hydroxybutyrate (BHOB), which is produced from the liver after moderate to prolonged food deprivation, appears to be a critical signal, linking defense against starvation with defense against infection. Activation of BHOB receptor GPR109A (also known as HCA2 or HCAR2) suppresses macrophage and monocyte response to LPS (Digby et al., 2012; Zandi-Nejad et al., 2013), inhibits progression of atherosclerosis (Lukasova et al., 2011), and inhibits lymphocyte infiltration in models of stroke and experimental autoimmune encephalomyelitis (Chen et al., 2014; Rahman et al., 2014). In a similar vein, BHOB has been shown to potently inhibit inflammasome activation in vitro and in vivo through a yet undetermined mechanism (Youm et al., 2015).

Second, because metabolic programs are so tightly coupled to immune response activation, metabolites may also act as a built-in mechanism for immune regulation. Metabolites, such as itaconate and lactate, generated specifically during an immune response or as byproducts of pathways essential for fueling immune activation accumulate over the course of the immune response (Lampropoulou et al., 2016; Pearce and Pearce, 2013). Immunosuppressive functions of these metabolites can then act as intrinsic regulators of the duration and magnitude of the response. Supporting this model is the fact that both itaconate and lactate, acting through the lactate receptor GPR81, have immunosuppressive functions (Hoque et al., 2014; Lampropoulou et al., 2016). Furthermore, lactate has been shown to polarize macrophages toward an M2 phenotype (Colegio et al., 2014).

Third, metabolites produced by the microbiota can be used by the immune system to monitor the quality of the microbial communities in colonized tissues. In this way, activation or suppression of immune and inflammatory pathways by microbial metabolites can play a role in shaping the microbiota composition: the metabolites associated with preferred microbial consortia would be expected to be anti-inflammatory, while metabolites produced by undesired microbes would be pro-inflammatory. Although there is growing evidence supporting the role of microbial metabolic signals in regulating host immunity, it is interesting to note that many of these metabolites signal through the receptors that detect endogenous (host-derived) metabolites.