Fueling defense: PPARα enhances macrophage inflammatory responses

While angiotensin-converting enzyme (ACE) is traditionally known for its ability to regulate blood pressure and fluid balance through the renin‒angiotensin system, ACE also plays a pivotal role in immune activation [1]. Macrophages in which ACE is overexpressed display enhanced inflammatory responses, as evidenced by increased antitumor and antibacterial activity [2]. This increase in inflammation coincides with increased lipid metabolism and ATP production [3, 4]. The mechanisms by which ACE enhances cellular metabolism and inflammation remain unknown. In this issue of Cellular and Molecular Immunology, Saito et al. [5] provide compelling evidence that peroxisome proliferator-activated receptor α (PPARα) is central to the observed enhanced immune capabilities of macrophages overexpressing ACE.

The inflammatory potential of macrophages is intrinsically tied to cellular metabolic processes, especially lipid metabolism. Macrophages rely on their metabolic adaptability to meet the demands of the diverse microenvironments in which they reside. Macrophage behavior and function are particularly regulated by lipid metabolism. Lipid metabolic pathways in alveolar macrophages and Kupffer cells accelerate their potential in maintaining tissue homeostasis by clearing lipids and apoptotic cells [6, 7]. Increased mitochondrial and lipid metabolism is usually associated with anti-inflammatory macrophage phenotypes [8–10]; however, recent work in obese white adipose tissue has shown that inflammatory macrophages can also rely on mitochondrial metabolism to process the lipid overload caused by overnutrition [11].

PPARα, a nuclear receptor and transcriptional regulator of fatty acid oxidation that is expressed mainly in the liver, is also expressed in other cell types, including macrophages. On the basis of the notion that PPARα protein levels increase upon ACE overexpression in macrophages, the authors questioned whether increased PPARα activity is key to the increased immune responses after ACE overexpression. To investigate this, they targeted PPARα in macrophages overexpressing ACE, confirming that PPARα plays an important role in the enhanced immune capacity exhibited by these macrophages. All phenotypic changes found in ACE-overexpressing macrophages, including increased ATP production and mitochondrial respiration, enhanced cytotoxicity against tumor cells and increased phagocytosis and killing of bacteria, are reversed upon PPARα deletion (Fig. 1).

Fig. 1.

ACE-overexpressing (ACE^O.E. macrophages in green) increases phagocytosis, bacterial killing and antitumor capacity, PPARα expression, ATP production and mitochondrial respiration in macrophages. This effect is reversed in macrophages overexpressing ACE with targeted deletion of PPARα (ACE^O.E. PPARα^del macrophages, in orange). Created in: https://BioRender.com

Although PPARα activation typically represses inflammation [12, 13], this study demonstrated its contribution to immune activation through enhanced metabolic fitness, challenging the conventional view that PPARα is solely anti-inflammatory. The findings of Saito et al. [5] emphasize the context-dependent role of transcription factors and metabolic pathways in macrophage biology. Enhanced metabolic fitness in ACE-overexpressing macrophages is characterized by increased ATP production and mitochondrial respiration in a PPARα-dependent manner [5]. Although prior (mostly) in vitro studies associated increased ATP production and mitochondrial respiration with anti-inflammatory macrophages [8, 9] and the suppression of inflammation [14], recent in vivo findings revealed a more nuanced, tissue- and context-dependent relationship [11]. In this specific context, increased metabolism, resulting in increased cellular fitness in ACE-overexpressing macrophages, is likely the primary driver of the observed increase in immune activity.

The ability of PPARα to enhance macrophage function has significant therapeutic implications. Supplementation of tumor-bearing mice with PPARα agonists can repress tumor growth not only in mice with ACE-overexpressing macrophages but also in wild-type mice. Interestingly, the observations initially observed in murine models also translate to human cells, underscoring that activation of this pathway provides potential new strategies for boosting macrophage-mediated antitumor responses in human diseases. PPARα agonists, such as fibrates, are already used to treat metabolic disorders such as dyslipidemia [15] and could be repurposed to increase immune responses in diseases such as cancer and chronic infections. However, the tissue- and disease-specific effects of PPARα activation must be carefully considered.

In conclusion, the study by Saito et al. identified a key role for PPARα in macrophage function, particularly in the context of ACE overexpression. Future research should aim to elucidate how ACE increases PPARα activity and to elucidate the molecular mechanisms by which PPARα enhances macrophage immune activation. By enhancing metabolic fitness, PPARα enables macrophages to mount more robust antitumor and antibacterial responses. These findings challenge the traditional view that PPARα is solely anti-inflammatory and open new avenues for therapeutic interventions. Future studies should further explore the promising potential of PPARα agonists in treating human diseases.

Competing interests

The author declares no competing interests.